In vivo selection of human embryonic stem cell-derived cells expressing methotrexate-resistant dihydrofolate reductase.

Human embryonic stem cells (hESCs) provide a novel source of hematopoietic and other cell populations suitable for gene therapy applications. Preclinical studies to evaluate engraftment of hESC-derived hematopoietic cells transplanted into immunodeficient mice demonstrate only limited repopulation. Expression of a drug-resistance gene, such as Tyr22-dihydrofolate reductase (Tyr22-DHFR), coupled to methotrexate (MTX) chemotherapy has the potential to selectively increase the engraftment of gene-modified, hESC-derived cells in mouse xenografts. Here, we describe the generation of Tyr22-DHFR-GFP-expressing hESCs that maintain pluripotency, produce teratomas and can differentiate into MTXr-hemato-endothelial cells. We demonstrate that MTX administered to nonobese diabetic/severe combined immunodeficient/IL-2Rgammac(null) (NSG) mice after injection of Tyr22-DHFR-hESC-derived cells significantly increases human CD34(+) and CD45(+) cell engraftment in the bone marrow (BM) and peripheral blood of transplanted MTX-treated mice. These results demonstrate that MTX treatment supports selective, long-term engraftment of Tyr22-DHFR cells in vivo, and provides a novel approach for combined human cell and gene therapy.

Phase II study of sunitinib in men with advanced prostate cancer.

BACKGROUND: This study explored the efficacy and tolerability of sunitinib, an inhibitor of tyrosine kinase receptors, in men with castration-resistant prostate cancer (CRPC). METHODS: Men with no prior chemotherapy (group A) and men with docetaxel (Taxotere)-resistant prostate cancer (group B) were treated with sunitinib. The primary end point was confirmed 50% prostate-specific antigen (PSA) decline. Secondary end points included objective response rate and safety. Serum-soluble biomarkers were measured. RESULTS: Seventeen men were enrolled in each group. One confirmed PSA response was observed in each group, and an additional eight men and seven men had stable PSA at week 12 in groups A and B, respectively. Improvements in imaging were observed in the absence of post-treatment PSA declines. Common adverse effects included fatigue, nausea, diarrhea, myelosuppression and transaminase elevation. Significant changes following sunitinib treatment were observed in serum-soluble biomarkers including soluble vascular endothelial growth factor receptor-2, platelet-derived growth factor aa, placental growth factor and leptin. CONCLUSIONS: Sunitinib monotherapy resulted in few confirmed 50% post-treatment declines in PSA in men with CRPC. Serum markers of angiogenesis confirmed on-target effects of sunitinib. Assessments of radiographic disease status were often discordant with changes in PSA, indicating that alternate end points are important in future trials.

Closed-system behaviour of the intra-crystalline fraction of amino acids in mollusc shells.

When mollusc shells are analysed conventionally for amino acid geochronology, the entire population of amino acids is included, both inter- and intra-crystalline. This study investigates the utility of removing the amino acids that are most susceptible to environmental effects by isolating the fraction of amino acids encapsulated within mineral crystals of mollusc shells (intra-crystalline fraction). Bleaching, heating and leaching (diffusive loss) experiments were undertaken on modern and fossil Corbicula fluminalis, Margaritifera falcata, Bithynia tentaculata and Valvata piscinalis shells. Exposure of powdered mollusc shells to concentrated NaOCl for 48 h effectively reduced the amino acid content of the four taxa to a residual level, assumed to represent the intra-crystalline fraction. When heated in water at 140 degrees C for 24 h, only 1% of amino acids were leached from the intra-crystalline fraction of modern shells compared with 40% from whole shell. Free amino acids were more effectively retained in the intra-crystalline fraction, comprising 55% (compared with 18%) of the whole shell after 24 h at 140 degrees C. For fossil gastropods, the inter-shell variability in D/L values for the intra-crystalline fraction of a single-age population was reduced by 50% compared with conventionally analysed shells. In contrast, analysis of the intra-crystalline fraction of C. fluminalis does not appear to improve the results for this taxon, possibly due to variability in shell ultrastructure. Nonetheless, the intra-crystalline fraction in gastropods approximates a closed system of amino acids and appears to provide a superior subset of amino acids for geochronological applications.

Challenges in the treatment of bladder cancer.

Seventy to eighty percent of patients with newly-diagnosed bladder cancer will present with superficial tumors (Ta, Tis or T(1)). There is, however, a continuum between superficial and muscle-invasive cancer, with the advanced cases usually associated with less-differentiated histology and aneuploidy. Common sites of metastasis include regional lymph nodes, bone, lung, skin and liver. From the low cure rates achieved with radical cystectomy, there is strong evidence that bladder cancer, from the outset, is a systemic disease. The limitations of local treatment are well-documented: a local control rate of 30% with radiation treatment, and 50-70% with radical cystectomy; and no improvement in surgical cure was seen with the use of preoperative radiation. Over the past 30 years, since the initial reports of the effectiveness of cisplatin in the treatment of advanced bladder cancer, there has been a steady flow of chemotherapeutic agents, singly and in combination, shown to be effective in the treatment of this tumor. While response rates and CR rates have increased with the use of combination chemotherapy, this has not translated into survival in advanced disease of greater than 16 months. While the search for more effective agents and combinations continues, attention has also been given to the roles of neoadjuvant and adjuvant chemotherapy in an effort to improve the cure rate achieved with surgery alone. Although radical cystectomy, with continent diversion or neobladder construction in selected cases remains the standard of care in the United States for patients with muscle-invasive bladder cancer, several groups have explored therapeutic strategies that aim at bladder preservation. Early approaches with the goal of bladder preservation consisted of radiation treatment as monotherapy (largely abandoned) or aggressive TURBT for smaller tumors. Over the past 20 years, the Massachusetts General Hospital (MGH) and the Radiation Therapy Oncology Group (RTOG) have studied patients with muscle-invading bladder cancer utilizing tri-modality treatment: a visibly complete transurethral resection followed by radiation with concurrent radiosensitizing chemotherapy and, subsequently, adjuvant chemotherapy. Thus, chemotherapy has been used in two phases of treatment (1) as radiosensitizers, given concurrently with radiation treatment and (2) as adjuvant treatment, recognizing that survival will only be improved by the successful treatment of micrometastases. Based on preliminary information from reports of the effectiveness of gemcitabine/cisplatin in advanced disease, that combination was chosen as the adjuvant regimen in one of our earlier protocols, recently completed and reported. Our current protocol utilizes the Bellmunt regimen as our adjuvant program with the highest RR in advanced disease. This study is ongoing, with early reports of tolerance of the three-drug regimen encouraging. The treatment options for muscularis propria-invasive bladder tumors can broadly be divided into those that spare the bladder and those that involve removing it. In the United States, radical cystectomy with pelvic lymph node dissection is the standard method used to treat patients with this tumor.

Finasteride and bicalutamide as primary hormonal therapy in patients with advanced adenocarcinoma of the prostate.

BACKGROUND: Medical or surgical castration is effective in advanced prostate cancer but with profound side-effects, particularly on sexual function. Effective, less toxic therapies are needed. This study examined whether the addition of finasteride to high-dose bicalutamide enhanced disease control, as measured by additional decreases in serum prostate-specific antigen (PSA). PATIENTS AND METHODS: Forty-one patients with advanced prostate cancer received bicalutamide (150 mg/day). Finasteride (5 mg/day) was added at first PSA nadir. Serum PSA was measured every 2 weeks until disease progression. Questionnaires were administered to assess sexual function. RESULTS: Median follow-up is 3.9 years. At the first PSA nadir, median decrease in PSA from baseline was 96.5%. Thirty of 41 patients (73%) achieved a second PSA nadir and median decrease of 98.5% from baseline. Median time to each nadir was 3.7 and 5.8 weeks, respectively. Median time to treatment failure was 21.3 months. Toxicities were minor, including gynecomastia. Seventeen of 29 (59%) and 12 of 24 (50%) men had normal sex drive at baseline and at second PSA nadir, respectively. One-third of men had spontaneous erection at both time points. CONCLUSION: Finasteride provides additional intracellular androgen blockade when added to bicalutamide. Duration of control is comparable to castration, with preserved sexual function in some patients.

Selective bladder preservation for muscle-invasive transitional cell carcinoma of the urinary bladder.

Invasive transitional cell carcinoma (TCC) of the urinary bladder is traditionally treated with radical cystectomy. This approach results in great morbidity and lifestyle changes, and approximately half of the patients treated in this way will experience recurrent TCC despite surgery. An alternative approach using selective bladder-preservation techniques incorporates transurethral resection of bladder tumours, radiation therapy, and chemotherapy. Over the past 20 years, international experience has demonstrated that this approach is feasible, safe, and well tolerated. Furthermore, the long-term outcomes of overall survival and disease-free survival compare favourably with the outcomes from radical cystectomy. The most important predictor of response is stage, with significantly higher long-term survival in patients with T2 disease. Another important positive predictor of complete response to therapy is the ability of the urologic oncologist to remove all visible tumour through a transurethral approach prior to initiation of radiation therapy. A negative predictive factor is the presence of hydronephrosis, and age and gender do not affect disease-free survival. The majority of patients who enjoy long-term survival do so with an intact native bladder. Quality of life studies have demonstrated that the retained bladder functions well in nearly all of these patients. Selective bladder preservation will not entirely take the place of radical cystectomy, but should be offered as an important alternative to patients newly diagnosed with muscle-invasive TCC.

Selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer.

OBJECTIVES: To evaluate the outcomes of patients with muscle-invasive Stage T2-4a bladder carcinoma managed by transurethral surgery and concurrent chemoradiation. METHODS: A total of 190 patients were treated on institutional prospective protocols using concurrent cisplatin-containing chemotherapy and radiotherapy after rigorous transurethral resection of the bladder tumor. Patients were re-evaluated by repeated biopsy and urine cytologic analysis after 40 Gy, with the initial tumor response guiding subsequent therapy. One hundred twenty-one patients with a complete response by cytologic and histologic examination and those medically unfit for cystectomy received boost chemoradiation to 64 to 65 Gy. Those patients without a complete response were advised to undergo radical cystectomy. A total of 66 patients (35%) ultimately underwent radical cystectomy; 41 for less than a complete response and an additional 25 for recurrent invasive tumors. The median follow-up was 6.7 years for all surviving patients. RESULTS: The 5 and 10-year actuarial overall survival rate was 54% and 36%, respectively (Stage T2, 62% and 41%; Stage T3-T4a, 47% and 31%, respectively). The 5 and 10-year disease-specific survival rate was 63% and 59% (Stage T2, 74% and 66%; Stage T3-T4a, 53% and 52%), respectively. The 5 and 10-year disease-specific survival rate for patients with an intact bladder was 46% and 45% (Stage T2, 57% and 50%; Stage T3-T4a, 35% and 34%), respectively. The pelvic failure rate was 8.4%. No patient required cystectomy because of bladder morbidity. CONCLUSIONS: The 10-year overall survival and disease-specific survival rates are comparable with the results reported for contemporary radical cystectomy for patients of similar clinical and pathologic stage. One third of patients treated on protocol with the goal of bladder sparing ultimately required a cystectomy. A trimodality approach with bladder preservation based on the initial tumor response is, therefore, safe, with most long-term survivors retaining functional bladders.

Human ES cells--haematopoiesis and transplantation strategies.

Human embryonic stem (ES) cells provide a novel opportunity to study early developmental events in a human system. We have used human ES cell lines, including clonally derived lines, to evaluate haematopoiesis. Co-culture of the human ES cells with irradiated bone marrow stromal cell lines in the presence of fetal bovine serum (FBS), but without other exogenous cytokines, leads to differentiation of the human ES cells within a matter of days. A portion of these differentiated cells express CD34, the best-defined marker for early haematopoietic cells. Haematopoietic colony-forming cells (CFCs) are demonstrated by methylcellulose assay. Myeloid, erythroid, megakaryocyte and multipotential CFCs can all be derived under these conditions. Enrichment of CD34+ cells derived from the human ES cells markedly increases the yield of CFCs, as would be expected for cells derived from adult bone marrow or umbilical cord blood. Transcription factors are also expressed in a manner consistent with haematopoietic differentiation. This system now presents the potential to evaluate specific conditions needed to induce or support events in early human blood development. Human ES cells are also a novel source of cells for transplantation therapies. The immunogenicity of ES cell-derived cells is unknown. The unique properties of ES cells afford the opportunity to explore novel mechanisms to prevent immune-mediated rejection. Potential strategies to overcome rejection will be presented, including creation of haematopoietic chimerism as a means to successfully transplant cells and tissues derived from human ES cells.

Neoadjuvant docetaxel followed by radical prostatectomy in patients with high-risk localized prostate cancer: a preliminary report.

Effective treatment options for high-risk localized prostate cancer are limited. Patients at high risk for recurrence include those with biopsy Gleason scores of 8 to 10, prostate specific antigen (PSA) levels > 20 ng/mL, and clinical stage T3 disease. Docetaxel chemotherapy is active in hormone-refractory prostate cancer, either combined with estramustine or used as a single agent. To determine if systemic therapy can improve the outcome of radical prostatectomy in men with high-risk localized prostate cancer, we are undertaking a pilot phase II clinical trial of weekly docetaxel at 36 mg/m(2) for up to 6 months, followed by surgery. Patients are monitored with weekly visits, monthly digital rectal examinations, PSA measurement, and testosterone tests, and endorectal magnetic resonance imaging done at baseline, after two cycles, and again after six cycles. To date, 15 patients have been enrolled, and 70 cycles of chemotherapy have been administered. Toxicity has been mostly grade 1 in intensity, and fatigue has been the most common grade 2 toxicity reported. The primary endpoint of the trial is measurement of pathologic complete response rate, for which data are not yet available. Recruitment to the trial is ongoing.

Selective bladder conservation using transurethral resection, chemotherapy, and radiation: management and consequences of Ta, T1, and Tis recurrence within the retained bladder.

OBJECTIVES: Although radical cystectomy remains the standard of care for invasive bladder cancer in the United States, many groups are exploring the use of trimodality therapy using transurethral resection of the bladder tumor, radiation, and chemotherapy in an attempt to spare patients the need for cystectomy. As transitional cell carcinoma often arises from a urothelial field change, there is concern that the retained bladder is at risk of subsequent superficial (Ta, T1, Tis) tumors, some of which may have lethal potential. This study reports the outcomes of those patients with superficial relapse of transitional cell carcinoma after trimodality therapy. METHODS: One hundred ninety patients were treated using a series of trimodality therapy protocols between 1986 and 1998. All patients received induction chemotherapy and radiation and were selected for bladder preservation on the basis of a cytologic and histologic complete response. One hundred twenty-one patients had a complete response and formed the subjects of this study. RESULTS: With a median follow-up of 6.7 years for patients still alive, 32 experienced a superficial relapse (26%). The median time to this failure was 2.1 years. Sixty percent of the superficial failures were carcinoma in situ (Tis) and 67% arose at the site of the original invasive tumor. The risk of superficial failure was higher among those who had Tis associated with their original muscle-invasive tumor. Twenty-seven of these 32 cases were managed conservatively with transurethral resection and intravesical therapy. The irradiated bladder tolerated this therapy well and only 3 patients required treatment breaks. The 5 and 8-year survival was comparable for those who experienced superficial failure (68% and 54%, respectively) and those who had no failure at all (n = 74, 69% and 61%, respectively). However, a substantially lower chance of being alive with the native bladder owing to the need for late salvage cystectomies (61% versus 34%) was found. Cystectomy became necessary in 31% (10 of 32) either because of additional superficial recurrence (n = 7) or progression to invasive disease (n = 3). CONCLUSIONS: A trimodality approach to transitional cell bladder cancer mandates lifelong cystoscopic surveillance. Although most completely responding patients retain their bladders free from invasive relapse, one quarter will develop superficial disease. This may be managed in the standard fashion with transurethral resection of the bladder tumor and intravesical therapies but carries an additional risk that late cystectomy will be required.

Hematopoietic colony-forming cells derived from human embryonic stem cells.

Human embryonic stem (ES) cells are undifferentiated, pluripotent cells that can be maintained indefinitely in culture. Here we demonstrate that human ES cells differentiate to hematopoietic precursor cells when cocultured with the murine bone marrow cell line S17 or the yolk sac endothelial cell line C166. This hematopoietic differentiation requires fetal bovine serum, but no other exogenous cytokines. ES cell-derived hematopoietic precursor cells express the cell surface antigen CD34 and the hematopoietic transcription factors TAL-1, LMO-2, and GATA-2. When cultured on semisolid media with hematopoietic growth factors, these hematopoietic precursor cells form characteristic myeloid, erythroid, and megakaryocyte colonies. Selection for CD34(+) cells derived from human ES cells enriches for hematopoietic colony-forming cells, similar to CD34 selection of primary hematopoietic tissue (bone marrow, umbilical cord blood). More terminally differentiated hematopoietic cells derived from human ES cells under these conditions also express normal surface antigens: glycophorin A on erythroid cells, CD15 on myeloid cells, and CD41 on megakaryocytes. The in vitro differentiation of human ES cells provides an opportunity to better understand human hematopoiesis and could lead to a novel source of cells for transfusion and transplantation therapies.

Multilineage differentiation from human embryonic stem cell lines.

Stem cells are unique cell populations with the ability to undergo both self-renewal and differentiation. A wide variety of adult mammalian tissues harbors stem cells, yet "adult" stem cells may be capable of developing into only a limited number of cell types. In contrast, embryonic stem (ES) cells, derived from blastocyst-stage early mammalian embryos, have the ability to form any fully differentiated cell of the body. Human ES cells have a normal karyotype, maintain high telomerase activity, and exhibit remarkable long-term proliferative potential, providing the possibility for unlimited expansion in culture. Furthermore, they can differentiate into derivatives of all three embryonic germ layers when transferred to an in vivo environment. Data are now emerging that demonstrate human ES cells can initiate lineage-specific differentiation programs of many tissue and cell types in vitro. Based on this property, it is likely that human ES cells will provide a useful differentiation culture system to study the mechanisms underlying many facets of human development. Because they have the dual ability to proliferate indefinitely and differentiate into multiple tissue types, human ES cells could potentially provide an unlimited supply of tissue for human transplantation. Though human ES cell-based transplantation therapy holds great promise to successfully treat a variety of diseases (e.g., Parkinson's disease, diabetes, and heart failure) many barriers remain in the way of successful clinical trials.

An organ-preserving approach to muscle-invading transitional cell cancer of the bladder.

Bladder-preserving treatment for muscle-invasive disease is based on the response of the tumor to induction combined modality therapy. In the future, an organ-conserving approach will be widely offered as a safe and reasonable alternative to radical cystectomy.

The National Bladder Cancer Group's experience: invasive and metastatic bladder cancer selected reports.

The National Bladder Cancer Group, a multidisciplinary organization that was originally the therapeutic arm of the National Bladder Cancer Project, reported the results of trials using cisplatin with and without cyclophosphamide in patients with advanced bladder cancer. The objective response rate in both arms was 16% of 109 patients with no difference between the arms. Other studies included cisplatin and irradiation for patients who had comorbid conditions that prevented cystectomy (local response--cT2 11/13 patients; cT3 & cT4 2/4 patients). Seventy patients were treated on the same protocol, and 33 were alive 4 years later. Complete response versus local failure produced 57% versus 11% at 4 years. After cessation of funding, the clinicians at the Massachusetts General Hospital agreed to follow a potentially bladder-sparing multimodality protocol, which stipulated that visible tumor be resected following which the patient received methotrexate, vinblastine and cisplatin (MCV), small-volume irradiation, and more cisplatin with midcourse cystectomy if local tumor persisted. Overall survival was 45%. The Radiation Therapy Oncology Group conducted a similar study omitting MCV from one arm. The 5-year survival rate was 38% with no advantage for either arm.

The initial results in muscle-invading bladder cancer of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response.

PURPOSE: To assess the safety, tolerance, and efficacy of transurethral surgery plus concomitant cisplatin, 5-fluorouracil (5-FU), and radiation therapy in conjunction with selective bladder preservation in patients with muscle-invading bladder cancer. Patients and Methods. Thirty-four eligible patients with clinical stage T2-T4a, Nx M0 bladder cancer without hydronephrosis were entered into a protocol aimed at selective bladder preservation. Treatment began with as complete a transurethral resection as possible followed by induction chemoradiation. This consisted of cisplatin 15 mg/m(2) i.v. and 5-fluorouracil (5-FU) 400 mg/m(2) i.v. in the mornings on d 1, 2, 3, 15, 16, and 17. On d 1, 3, 15, and 17, radiation was given immediately following the chemotherapy using twice-a-day 3 Gy per fraction cores to the pelvis for a total radiation dose of 24 Gy. Response was evaluated by cystoscopy, cytology, and rebiopsy four weeks later. Patients with a complete response received consolidation therapy with the same drugs and doses on d 1, 2, 3, 15, 16, and 17 combined with twice-daily radiation therapy to the bladder and bladder tumor volume of 2.5 Gy per fraction for a total consolidation dose of 20 Gy and a total induction plus consolidation dose to the bladder and bladder tumor of 44 Gy. Patients who did not achieve a complete response were advised to undergo prompt cystectomy, as were those with a subsequent invasive recurrence. The median follow up is 29 months. RESULTS: Of the 34 eligible patients, 26 had a visibly complete transurethral resection. One patient did not complete induction treatment due to acute hematologic toxicity. After induction treatment, 22 (67%) of the 33 patients had no tumor detectable on urine cytology or rebiopsy. Of the 11 patients who still had detectable tumor, six underwent radical cystectomy and five underwent consolidation chemoradiation (one because of refusal to have the recommended cystectomy and four because the treating institutions erroneously assigned them to receive consolidation chemoradiation rather than cystectomy). No patient has required a cystectomy for radiation toxicity. Six patients have died of bladder cancer. The actuarial overall survival at three years is 83%. The probability of surviving with an intact bladder is 66% at three years. A total of seven patients (21%) developed grade 3 or grade 4 hematologic toxicity in conjunction with this treatment. CONCLUSION: This aggressive protocol comprising local surgery plus concurrent 5-FU, cisplatin, and high-dose hypofractionated radiation has been associated with moderately severe hematologic toxicity. Longer follow-up will be necessary to assess efficacy. Both the 67% complete response rate to induction therapy and the 66% three-year survival with an intact bladder are encouraging.

Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear hormone receptor that plays a key role in the differentiation of adipocytes. Activation of this receptor in liposarcomas and breast and colon cancer cells also induces cell growth inhibition and differentiation. In the present study, we show that PPARgamma is expressed in human prostate adenocarcinomas and cell lines derived from these tumors. Activation of this receptor with specific ligands exerts an inhibitory effect on the growth of prostate cancer cell lines. Further, we show that prostate cancer and cell lines do not have intragenic mutations in the PPARgamma gene, although 40% of the informative tumors have hemizygous deletions of this gene. Based on our preclinical data, we conducted a phase II clinical study in patients with advanced prostate cancer using troglitazone, a PPARgamma ligand used for the treatment of type 2 diabetes. Forty-one men with histologically confirmed prostate cancer and no symptomatic metastatic disease were treated orally with troglitazone. An unexpectedly high incidence of prolonged stabilization of prostate-specific antigen was seen in patients treated with troglitazone. In addition, one patient had a dramatic decrease in serum prostate-specific antigen to nearly undetectable levels. These data suggest that PPARgamma may serve as a biological modifier in human prostate cancer and its therapeutic potential in this disease should be further investigated.

Organ-conserving approaches to muscle-invasive bladder cancer: future alternatives to radical cystectomy.

In the USA radical surgery remains the golden standard for invasive bladder cancer. Yet in most other areas of surgical oncology the trend of the 1990s has been towards organ conservation with chemoradiation with or without limited local surgery. Patients with breast, oesophageal, anal, lung and larynx cancer are routinely offered conservative therapies as valid options in the management of their diseases but bladder stands apart from the crowd. Evidence is presented here to show that this need not be the case. Four older randomized trials failed to show a survival advantage when immediate cystectomy was compared with radiation followed by salvage cystectomy, if required. Five and 8-year survival rates for clinically staged patients treated by transurethral resection and chemoradiation (trimodality therapy) in several modern, large and mature series show survival rates comparable to those reported in contemporary radical cystectomy series. Eighty per cent of those alive 5 years after chemoradiation still retain their native bladder. Although superficial relapse occurs in 20% of cases, it remains responsive to BCG (Bacilles bilie de Calmette-Guerin) in the manner of de novo superficial disease. Quality-of-life studies show that the retained bladder functions well. At the Massachusetts General Hospital and in the multicentre prospective trials, less than 1% of patients needed cystectomy for bladder morbidity. It is of note that continent diversions may be performed as salvage after contemporary radiation therapy. Trimodality therapy is a novel and contemporary approach that owes little to the radiation treatment offered in the 1970s. While it will never entirely take the place of radical cystectomy, it should be offered as a reasonable alternative to patients with a new diagnosis of bladder cancer. This multidisciplinary approach will allow uro-oncology to keep in step with the oncological vanguard.

Does postoperative irradiation play a role in the adjuvant therapy of stage T4 colon cancer?

PURPOSE: This study analyzes the long-term outcome of patients with stage T4 colon cancer who receive postoperative irradiation. The purpose of the study is to define the potential role of this modality with current systemic therapies. PATIENTS AND METHODS: A retrospective analysis was performed of 152 patients undergoing resection of T4 colon cancer followed by moderate- to high-dose postoperative tumor bed irradiation with and without 5-fluorouracil-based chemotherapy. Of the 152 patients, 110 patients (T4N0 or T4N+) were treated adjuvantly, whereas 42 patients received irradiation for the control of gross or microscopic residual local tumor. RESULTS: For 79 adjuvantly treated patients with stage T4N0 or T4N+ cancer with one lymph node metastasis, the 10-year actuarial rates of local control and recurrence-free survival were 88% and 58%, respectively. Results were less satisfactory for patients with more extensive nodal involvement. The 10-year actuarial rates of local control and recurrence-free survival of 39 patients with T4 tumors complicated by perforation or fistulas were 81% and 53%, respectively. For 42 patients with incompletely resected tumors, the 10-year actuarial recurrence-free survival was 19%. CONCLUSIONS: In comparison with historical controls, postoperative tumor bed irradiation improves local control for some subsets of patients. In addition to standard 5-fluorouracil-based chemotherapy, adjuvant tumor bed irradiation should be considered when colon cancers invade adjoining structures, when they are complicated by perforation or fistulas, or when they are incompletely excised at the primary site.