Clinically decisive (dis)agreement in multidisciplinary team assessment of esophageal squamous cell carcinoma; a prospective, national, multicenter study.

BACKGROUND: Decisions regarding tumor staging, operability, resectability, and treatment strategy in patients with esophageal cancer are made at multidisciplinary team (MDT) conferences. We aimed to assess interobserver agreement from four national MDT conferences and whether this would have a clinical impact. METHODS: A total of 20 patients with esophageal cancer were included across all four upper gastrointestinal (GI) cancer centers. Fully anonymized patient data were distributed among the MDT conferences which decided on TNM category, resectability, operability, curability, and treatment strategy blinded to each other's decisions. The interobserver agreement was expressed as both the raw observer agreement and with Krippendorff's α values. Finally, a case-by-case evaluation was performed to determine if disagreement would have had a clinical impact. RESULTS: A total of 80 MDT evaluations were available for analysis. A moderate to near-perfect observer agreement of 79.2%, 55.8%, and 82.5% for TNM category was observed, respectively. Substantial agreement for resectability and moderate agreement for curability were found. However, an only fair agreement was observed for the operability category. The treatment strategies had a slight agreement which corresponded to disagreement having a clinical impact in 12 patients. CONCLUSIONS: Esophageal cancer MDT conferences had an acceptable interobserver agreement on resectability and TM categories; however, the operability assessment had a high level of disagreement. Consequently, the agreement on treatment strategy was reduced with a potential clinical impact. In future MDT conferences, emphasis should be on prioritizing the relevant information being readily available (operability, T & M categories) to minimize the risk of disagreement in the assessments and treatment strategies, and thus, delayed or suboptimal treatment.

Long-term follow-up of custom cross-pin fixation of 56 tumour endoprosthesis stems: a single-institution experience.

AIMS: Aseptic loosening is a major cause of failure in cemented endoprosthetic reconstructions. This paper presents the long-term outcomes of a custom-designed cross-pin fixation construct designed to minimize rotational stress and subsequent aseptic loosening in selected patients. The paper will also examine the long-term survivorship and modes of failure when using this technique. PATIENTS AND METHODS: A review of 658 consecutive, prospectively collected cemented endoprosthetic reconstructions for oncological diagnoses at a single centre between 1980 and 2017 was performed. A total of 51 patients were identified with 56 endoprosthetic implants with cross-pin fixation, 21 of which were implanted following primary resection of tumour. Locations included distal femoral (n = 36), proximal femoral (n = 7), intercalary (n = 6), proximal humeral (n = 3), proximal tibial (n = 3), and distal humeral (n = 1). RESULTS: The median follow-up was 132 months (interquartile range (IQR) 44 to 189). In all, 20 stems required revision: eight for infection, five for structural failure, five for aseptic loosening, and two for tumour progression. Mechanical survivorship at five, ten, and 15 years was 84%, 78%, and 78%, respectively. Mechanical failure rate varied by location, with no mechanical failures of proximal femoral constructs and distal femoral survivorship of 82%, 77%, and 77% at five, ten, and 15 years. The survivorship of primary constructs at five years was 74%, with no failure after 40 months, while the survivorship for revision constructs was 89%, 80%, and 80% at five, ten, and 15 years. CONCLUSION: The rate of mechanical survivorship in our series is similar to those reported for other methods of reconstruction for short diaphyseal segments, such as compressive osseointegration. The mechanical failure rate differed by location, while there was no substantial difference in long-term survival between primary and revision reconstructions. Overall, custom cross-pin fixation is a viable option for endoprosthetic reconstruction of short metaphyseal segments with an acceptable rate of mechanical failure. Cite this article: Bone Joint J 2019;101-B:724-731.

Population screening for the mutation associated with osteogenesis imperfecta in dachshunds.

Osteogenesis imperfecta (OI) is a genetic disorder causing defects in the development of collagen type I. Clinical signs of affected dachshunds include multiple fractures of bones, joint hyperlaxity and dentinogenesis imperfecta. Recently, a recessive mutation in the SERPINH1 gene was detected in dachshunds and enabled the development of a DNA test to identify dachshunds carrying the mutation. The purpose of the present study was to analyse the dachshund breeding population for the frequency of the SERPINH1 mutation among the nine different breed varieties in dachshunds, birth years and countries of origin. We genotyped the OI-associated SERPINH1 mutation in 1352 dachshunds from 12 different European countries including all nine varieties. Genotyping was done using a restriction fragment length polymorphism validated by DNA sequence analysis. The overall frequency of OI carriers was 12.9 per cent. Across all different size varieties, the SERPINH1 mutation was over-represented in wire-haired dachshunds with 17.3 per cent OI carriers. Among the different countries, the proportion of OI carriers was highest in Germany with 20.4 per cent. The test is useful for dachshund breeders to prevent the occurrence of OI-affected dogs and as a diagnostic tool for veterinarians.

Limitations of balloon sinuplasty in frontal sinus surgery.

Balloon sinuplasty is a tool that is used to treat selected patients with paranasal sinus pathologies. No studies have investigated the aetiology of failed access to the frontal sinus. The aim of our study was to specify the intraoperative technical failure rate and to analyse the aetiology of the failed access to predict potential technical difficulties before surgery. We retrospectively analysed the charts of patients who underwent balloon sinuplasty from November 2007 to July 2010 at three different ENT-Centres. CT-analysis of the patients with failed access was performed. Of the 104 frontal sinuses, dilation of 12 (12%) sinuses failed. The anatomy of all failed cases revealed variations in the frontal recess (frontoethmoidal-cell, frontal-bulla-cell or agger-nasi-cell) or osteoneogenesis. In one patient, a lymphoma was overlooked during a balloon only procedure. The lymphoma was diagnosed 6 months later with a biopsy during functional endoscopic sinus surgery. In complex anatomical situations of the frontal recess, balloon sinuplasty may be challenging or impossible. In these situations, it is essential to have knowledge of classical functional endoscopic sinus surgery of the frontal recess area. The drawbacks of not including a histopathologic exam should be considered in balloon only procedures.

Minimally invasive diagnosis of sarcoidosis by EBUS when conventional diagnostics fail.

BACKGROUND: Endobronchial ultrasound-guided transbronchial fine-needle aspiration (EBUS) is a minimally invasive method used routinely for mediastinal staging of patients with lung cancer. EBUS has also proved to be a valuable diagnostic tool for patients with different intrathoracic lesions who remain undiagnosed despite bronchoscopy and CT-guided fine-needle aspiration. OBJECTIVE: The present study focused on EBUS for diagnosing sarcoidosis. DESIGN: During a 3-year period 308 of 601 patients who underwent EBUS at our institution were referred for further diagnostic of a radiologically suspicious lesion in the lung parenchyma (n = 195), enlarged lymph nodes in the mediastinum (n = 89), a suspicious tumor in the mediastinum or pleural disease (n = 24) but no one had a definite histological diagnosis. All charts were reviewed retrospectively. RESULTS: Of the 308 patients 43 (14%) were eventually diagnosed with sarcoidosis. Thirty-three (77%) were diagnosed with EBUS. In the remaining 10 patients EBUS did not provide adequate tissue samples in 4 (9%) and in 6 patients (14%) EBUS provided adequate tissue but no definite diagnosis. EBUS was significantly better to establish the diagnosis in patients with enlarged mediastinal lymph nodes compared with isolated lung parenchymal involvement (85% vs 63%, p < 0.05). CONCLUSION: EBUS is a valuable minimally invasive diagnostic modality to establish the diagnosis of sarcoidosis of unselected patients with undiagnosed intrathoracic lesions after conventional work up--particularly if patients have enlarged mediastinal lymph nodes. This minimally invasive procedure provides a final diagnosis without exposing the patient to the risk of complications from more invasive procedures.

Impact of the lower energy threshold on the NEMA NU2-2001 count-rate performance of a LSO based PET-CT scanner.

UNLABELLED: The aim of this study was to investigate the impact of the lower energy threshold (LET) on the NEMA NU2-2001 count-rate performance of a LSO-based PET scanner (Siemens PET-CT Biograph Sensation 16). The quantitative measurements were focused on three different aspects: noise equivalent count rate (NEC), scatter fraction, and absolute sensitivity. METHODS: According to the NEMA-NU2-2001 protocol count-rate-performance (NEC-2R, scatter fraction) and sensitivity were evaluated performing serial measurements at LETs of 350, 375, 400, 410, 420, 430, 440, and 450 keV (the upper energy threshold was fixed to 650 keV). NEMA protocols were adapted to account for the intrinsic radioactivity of (176)Lu in the LSO crystals. RESULTS: Up to a radioactivity concentration of 8 kBq/ml the highest NEC-rates were obtained at an LET of 410 keV, between 8 and 20 kBq/ml at an LET of 420 keV and above 20 kBq/ml at an LET of 430 keV. The overall NEC maximum was 67 kcps at 430 keV (at 28 kBq/ml). The minimum scatter fraction was measured at a radioactivity concentration of approximately 0.5 kBq/ml. The scatter fraction decreased continuously from 45% at an energy threshold of 350 keV to 24% at 450 keV. The maximum sensitivity of 5.8 kcps/MBq, was obtained at an LET of 350 keV and the minimum sensitivity of 4.2 kcps/MBq at an LET of 450 keV. At the LET with the maximum NEC-rate (430 keV) the sensitivity was 4.8 kcps/MBq. CONCLUSION: The optimal count-rate performance of the LSO-based PET system was found at LETs between 410 keV and 430 keV depending on the actual radioactivity concentration placed in the scanner. A global maximum in NEC count rate was obtained at an LET of 430 keV.

Challenging the platinum combinations in the chemotherapy of NSCLC.

In previously untreated patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) the combination of docetaxel and gemcitabine is active and well tolerated. In the phase II setting using a 3-week schedule, response rates (RR) ranged from 25 to 50%, and median survival from 11 to 13 months. Preliminary data with weekly and bi-weekly schedules indicate maintained efficacy while reducing the risk of neutropenia. A randomized phase III trial has shown that the combination of docetaxel and gemcitabine is as active as docetaxel plus cisplatin, achieving a 1-year survival rate of 39%, with significantly less neutropenia and gastro-intestinal toxicity. The combination of docetaxel with vinorelbine is equally active and the associated toxicities are manageable. In phase II studies the average response rate is 40%, and in one study using a 2-week schedule the 1-year survival rate was 60%. With this combination neutropenia is the commonest adverse event while clinically significant neuropathy is infrequent. In a randomized phase II trial, docetaxel plus cisplatin was compared to docetaxel plus irinotecan. The non-platinum doublet achieved comparable levels of activity, though with a different toxicity profile (more diarrhea but less nausea and vomiting). The combination of docetaxel with irinotecan and carboplatin has achieved 1-year survival of 55%. All three docetaxel combinations (gemcitabine, vinorelbine, and irinotecan) could provide a valuable alternative to platinum-based chemotherapy and should be further evaluated in phase III setting.

Patellar metastasis from a squamous carcinoma of the lung: a case report.

Bone is a common site of metastasis from lung cancer. Metastasis to the patella, however, is rare. A 76-year-old man presented with knee pain caused by an isolated patellar metastasis from squamous cell carcinoma of the lung. Treatment was delayed secondary to delay in diagnosis. In cases of bone pain that are unexplained or out of proportion to a traumatic event, more extensive diagnostic studies should be done.

Feasibility of oral topotecan plus intravenous paclitaxel in advanced non-small-cell lung cancer.

Standard chemotherapy regimens in non-small-cell lung cancer (NSCLC) are platinum-based (cisplatin, carboplatin), with inherent, well-known antitumor activity and toxicity. However, the availability of new agents with novel mechanisms of action and activity in a range of tumor types, coupled with suboptimal activity of single-agent therapy, have prompted the investigation of multidrug regimens in the treatment of NSCLC. One potential combination regimen, in which each agent has antitumor activity in NSCLC monotherapy, is topotecan plus paclitaxel. This article will review the feasibility and tolerability of an oral formulation of topotecan (1.0-1.5 mg/m(2)/day x 5 days) administered with intravenous paclitaxel (175 mg/m(2) as a 3-hour infusion on day 1) in advanced NSCLC patients. The maximum tolerated dose of oral topotecan will be reported, along with preliminary response and tolerability data.

Feasibility of oral topotecan in previously untreated patients with small-cell lung cancer ineligible for standard therapy.

The single-agent activity of intravenous (i.v.) topotecan has been established in small-cell lung cancer (SCLC), with overall tumor responses of 39% in previously untreated patients and 11-37% in relapsed patients. An oral formulation of topotecan has been developed that is more convenient for patients, which may lead to greater compliance and greater prescribing flexibility for use in combination with other active agents. We initiated a phase II trial to test the feasibility of oral topotecan administered at 2.0 mg/m(2) on days 1-5 of a 21-day cycle in previously untreated SCLC patients. Patients received a median of 5 courses of oral topotecan. Grade 3/4 myelosuppression was common in patients treated with 2.0 mg/m(2); secondary to 2 patients developing fatal sepsis, patients enrolled later in the study were treated at 1.7 mg/m(2). At both doses, the majority of nonhematologic toxicity was grade 1/2 in severity, and there were no discontinuations attributed to nonhematologic toxicity. In a patient population reflective of the general SCLC population (i.e. elderly with multiple comorbidities), oral topotecan was generally well tolerated at the lower dose level, with a preliminary antitumor activity profile comparable to i.v. topotecan. Clinical studies are currently under way to compare the antitumor activity of oral topotecan with i.v. topotecan in second-line SCLC and investigate oral topotecan in combination with other active agents in SCLC.

Phase II trial of CI-980 in patients with disseminated malignant melanoma and no prior chemotherapy. A Southwest Oncology Group study.

Malignant melanoma is increasing in frequency at a rapid rate in the United States. Metastatic disease is chemoresistant with DTIC considered the most active single agent. CI-980 is a synthetic mitotic inhibitor that blocks the assembly of tubulin and microtubules. It has shown cytotoxic activity against a broad spectrum of murine and human tumor cell tines. CI-980 can cross the blood brain barrier, is effective when given orally or parenterally, and is active against multidrug resistant cell lines overexpressing P-glycoprotein. In this trial, patients with disseminated melanoma with measurable disease, SWOG performance status of 0-1, no prior chemotherapy or immunotherapy for metastatic disease, and adequate hepatic and renal function, were enrolled. Treatment with CI-980 was given by 72 h continuous i.v. infusion at a dose of 4.5 mg/m2/day, days 1-3 every 21 days. Twenty-four patients were registered on this study with no patients ineligible. They ranged in age from 33-78 with performance status of 0 in 15 patients and 1 in 9 patients. Nineteen patients had visceral disease with 12 having liver involvement. There were no confirmed responses. The overall response rate was 0% (95% CI 0%-14%). The median overall survival is eleven months (95% CI 4-14 months). The most common toxicities were hematologic and consisted of leukopenia/granulocytopenia and anemia, with nausea/vomiting and malaise/fatigue/weakness also frequent. CI-980 administered at this dose and schedule has insufficient activity in the treatment of disseminated malignant melanoma to warrant further investigation.

Treatment-induced pathologic necrosis: a predictor of local recurrence and survival in patients receiving neoadjuvant therapy for high-grade extremity soft tissue sarcomas.

PURPOSE: To determine whether treatment-induced pathologic necrosis correlates with local recurrence and overall survival in patients who receive neoadjuvant therapy for high-grade extremity soft tissue sarcomas. PATIENTS AND METHODS: Four hundred ninety-six patients with intermediate- to high-grade extremity soft tissue sarcomas received protocol neoadjuvant therapy. All patients underwent surgical resection after neoadjuvant therapy and had pathologic assessment of tumor necrosis in the resected specimens. RESULTS: The 5- and 10-year local recurrence rates for patients with > or = 95% pathologic necrosis were significantly lower (6% and 11%, respectively) than the local recurrence rates for patients with less than 95% pathologic necrosis (17% and 23%, respectively). The 5- and 10-year survival rates for the patients with > or = 95% pathologic necrosis were significantly higher (80% and 71%, respectively) than the survival rates for the patients with less than 95% pathologic necrosis (62% and 55%, respectively). Patients with less than 95% pathologic necrosis were 2.51 times more likely to develop a local recurrence and 1.86 times more likely to die of their disease as compared with patients with > or = 95% pathologic necrosis. The percentage of patients who achieved > or /= 95% pathologic necrosis increased to 48% with the addition of ifosfamide as compared with 13% of the patients in all the other protocols combined. CONCLUSION: Treatment-induced pathologic necrosis is an independent predictor of both local recurrence and overall survival in patients who receive neoadjuvant therapy for high-grade extremity soft tissue sarcomas. A complete pathologic response (> or = 95% pathologic necrosis) correlated with a significantly lower rate of local recurrence and improved overall survival.

Challenging the platinum combinations: docetaxel (Taxotere) combined with gemcitabine or vinorelbine in non-small cell lung cancer.

The limited single-agent activity of cisplatin, its toxicity profile, and the inconvenience involved in hydrating patients has compelled researchers to investigate other treatments as possible alternative therapies in non-small cell lung cancer. More recently, interest has focused on the potential of nonplatinum combinations. Phase II studies show that the combination of docetaxel (Taxotere; Aventis, Antony, France) and gemcitabine is active in stage IIIB/IV non-small cell lung cancer not previously treated by chemotherapy. Response rates of up to 54% and a median survival time of 13 months have been reported. These data are comparable with the achievements of cisplatin-based combinations. A randomized phase II trial of docetaxel plus gemcitabine versus docetaxel plus cisplatin found that the two regimens were equally active in terms of response rate, median, and 1-year survival. However, the combination of docetaxel with gemcitabine produced significantly less neutropenia and nonhematologic toxicities. In combination, from 80% to 100% of the full single-agent gemcitabine and docetaxel doses can safely be administered once every 3 weeks. The combination of docetaxel plus vinorelbine is also active in non-small cell lung cancer and preliminary data suggest that this schedule with prophylactic filgrastim may optimize tolerability and dose intensity. In a phase II study using this approach, a confirmed response rate of 51% was obtained in 35 patients. At 12 months, the predicted median survival is 14 months and the predicted 1-year survival rate is 60%. Excessive lacrimation, fatigue, and onycholysis were cumulative toxicities. However, the incidence of mucositis and neuropathy was low with the combination of docetaxel and vinorelbine. Docetaxel combined with other new agents, particularly gemcitabine, may offer another useful alternative to cisplatin-based chemotherapy in patients with good performance status.

Soft tissue echinococcosis: a report of two cases and review of the literature.

Echinococcosis (hydatid cyst disease) is a zoonotic infection caused by the parasitic tapeworm Echinococcus. The larval stage of this parasite can implant in many organs of the body, most commonly the liver, and create internal budding cystic masses. Echinococcal cysts also can implant in soft tissues; however, a review of the literature revealed no published case with the patient initially presenting with a soft tissue mass. Two such cases are reported in the current study. Physicians who evaluate soft tissue masses, particularly in patients from Echinococcus-endemic areas, need to include echinococcosis in their differential diagnoses. The current treatment of choice for soft tissue echinococcosis is wide resection combined with perioperative medical therapy.

Tibial turn-up for long distal femoral bone loss.

Since 1990, seven patients have been treated by the authors with the tibial turn-up procedure. They have ranged in age from 8 to 37 years; four were skeletally mature adults and three were children. All seven patients were faced with a clinical situation that required surgical removal of a long portion of their affected distal femur. Three of the adult patients initially were treated for osteosarcoma with long distal femoral resections and allograft arthrodesis of the knee. The allografts ultimately failed, two because of aseptic failure and one because of infection. One patient required distal femoral removal for chronic osteomyelitis and pathologic fracture. Of the three children who were treated, two had turn-ups after long resection of the distal femur for bone malignancy, and one had a secondary turn-up after failure of a long distal femoral endoprosthesis. The technique uses the normal ipsilateral tibia as a vascularized pedicle graft to restore femoral length. The ultimate result, even after very high above knee resection, is a long above knee amputation stump. The followup of the patients in the current study ranged from 2 to 8 years. All patients achieved healing and were able to wear above knee prostheses. The tibial turn-up is an effective procedure that results in a long functional above knee amputation stump even after very high above knee resections.

High-activity samarium-153-EDTMP therapy followed by autologous peripheral blood stem cell support in unresectable osteosarcoma.

PURPOSE: Despite highly efficacious chemotherapy, patients with osteosarcomas still have a poor prognosis if adequate surgical control cannot be obtained. These patients may benefit from therapy with radiolabeled phosphonates. PATIENTS AND METHODS: Six patients (three male, three female; seven to 41 years) with unresectable primary osteosarcoma (n = 3) or unresectable recurrent sites of osteosarcomas (n = 3) were treated with high-activity of Sm-153-EDTMP (150 MBq/kg BW). In all patients autologous peripheral blood stem cells had been collected before Sm-153-EDTMP therapy. RESULTS: No immediate adverse reactions were observed in the patients. In one patient bone pain increased during the first 48 hrs after therapy. Three patients received pain relief. Autologous peripheral blood stem cell reinfusion was performed on day +12 to +27 in all patients to overcome potentially irreversible damage to the hematopoietic stem cells. In three patient external radiotherapy of the primary tumor site was performed after Sm-153-EDTMP therapy and in two of them polychemotherapy was continued. Thirty-six months later one of these patients is still free of progression. Two further patients are still alive. However, they have developed new metastases. The three patients who had no accompanying external radiotherapy, all died of disease progression five to 20 months after therapy. CONCLUSION: These preliminary results show that high-dose Sm-153-EDTMP therapy is feasible and warrants further evaluation of efficacy. The combination with external radiation and polychemotherapy seems to be most promising. Although osteosarcoma is believed to be relatively radioresistant, the total focal dose achieved may delay local progression or even achieve permanent local tumor control in patients with surgically inaccessible primary or relapsing tumors.

Imaging of surgical paraphernalia: what belongs in the patient and what does not.

Many radiologists are not familiar with the names of various instruments, surgical sponges, and needles that may be seen on intraoperative and postoperative radiographs. These devices may be intentionally placed for localization or therapeutic intervention, discovered on radiographs obtained to evaluate incorrect sponge or needle counts, or incidentally encountered on postoperative radiographs. These paraphernalia are usually described in vague nonspecific terms in radiology reports. In this article, photographs and radiographs of several instruments commonly used for intraoperative localization or therapy are presented, as well as examples of sponges, needles, and other devices that should not be found on postoperative radiographs. Familiarity with their appearances will allow a more precise and knowledgeable description in radiology reports.

Primary osteosarcoma of a metatarsal bone.

Although osteosarcoma is the most common primary bone malignancy of childhood and adolescence that is not related to marrow cells, involvement of the short tubular bones is uncommon. In contrast to more conventional sites, where the tumor is usually high grade and found in adolescents, osteosarcoma of the small bones is more likely to be low grade, and is often seen in older individuals. We present a case of low-grade primary osteosarcoma of a metatarsal bone in a 25-year-old woman.

Expandable endoprosthesis reconstruction in skeletally immature patients with tumors.

Between September 1984 and January 1996, 32 expandable endoprostheses were used for limb reconstruction after resection of malignant bone tumors in patients who were skeletally immature. The 20 boys and 12 girls ranged in age from 3 to 15 years (mean, 9.7 years). One patient had a Stage IIA tumor, 22 patients had Stage IIB tumors, and seven patients had Stage III tumors according to the classification of the Musculoskeletal Tumor Society. There also were two patients with parosteal osteosarcomas. The histologic diagnosis was osteosarcoma in 23 patients and Ewing's sarcoma in nine. All patients except the patients with parosteal osteosarcoma received standard neoadjuvant therapy. Twenty-two Lewis Expandable Adjustable Prostheses, four modular Wright Medical prostheses, four modular Howmedica prostheses, and two Techmedica expandable prostheses were used. Thirteen patients died, two have no evidence of disease, and 17 are continuously disease free. Sixteen of 32 patients (50%) have not had an expansion procedure because of early death in 10 and early amputation in three. Three patients are waiting to undergo an expansion procedure. Sixteen of the 32 patients (50%) have undergone 32 expansion procedures, to a maximum of 9 cm, without any infection. To maintain range of motion before the expansion procedure, a complete resection of the pseudocapsule was done routinely. Fourteen of the 32 patients did not have complications. Eighteen of the 32 patients had 27 complications. All Lewis Expandable Adjustable Prosthesis endoprostheses and the two nonmodular Techmedica prostheses were associated with a large amount of titanium debris. The children's functional results were similar to the results reported for adults with an average Musculoskeletal Tumor Society rating of good to excellent at the knee, fair to good at the hip, and fair about the shoulder. Rehabilitation of the knee in very young patients (5-8 years) remains problematic and careful selection of patient and family is necessary. The Lewis Expandable Adjustable Prosthesis probably should be reserved for very young patients (5-8 years) and modular systems should be used for large preadolescent and adolescent children.

Single-agent gemcitabine and gemcitabine/irinotecan combination (irimogem) in non-small cell lung cancer.

Gemcitabine is a fluoridated pyrimidine related to cytosine arabinoside that has significant activity in solid tumor models. Irinotecan is a camptothecin analog with an active metabolite, SN-38, which inhibits topoisomerase I activity by stabilizing the topoisomerase I-DNA cleavable complex. Gemcitabine studies in non-small cell lung cancer conducted in the United States, as well as an international collaboration and clinical trials from Europe and Japan, found overall response rates of 20% to 26%, a median duration of response between 5 to 9 months, and a median duration of survival ranging from 7 to 12.3 months. Gemcitabine also has been shown to be more effective than best supportive care in non-small cell lung cancer. In a phase I trial of irinotecan (50, 75, 100, and 115 mg/m2) in combination with 1,000 mg/m2 gemcitabine, three patients had documented partial responses: one with pancreas cancer at irinotecan 100 mg/m2, one with pancreas cancer, and one with metastatic carcinoma of unknown primary at irinotecan 115 mg/m2. Three of five non-small cell lung cancer patients had stable disease for four or more cycles at irinotecan doses of 50, 75, and 100 mg/m2; no non-small cell lung cancer patients were treated at irinotecan 115 mg/m2. We recommend that a combination of gemcitabine 1,000 mg/m2 and irinotecan 100 mg/m2 given on days 1 and 8 every 3 weeks be used as the starting dose in future phase II studies. Furthermore, based on the absence of severe nonhematologic toxicity or grade IV hematologic toxicity in the majority of patients treated at the highest dose, escalation of irinotecan to 115 mg/m2 may be considered for subsequent cycles in patients who do not experience > or =grade I hematologic or non-hematologic toxicity during the first cycle of gemcitabine/irinotecan combination chemotherapy.