Phase I study of gemcitabine and radiotherapy plus cisplatin after transurethral resection as conservative treatment for infiltrating bladder cancer

PURPOSE: Although the use of radical transurethral resection followed by concurrent radiochemotherapy leads to a similar survival rate to that achieved after cystectomy, the number of long-term survivors is low in both cases. An improvement may be obtained by adding a new drug, such as gemcitabine, which is active in bladder cancer and acts as a radiosensitizer. However, because gemcitabine may be very toxic when associated with radiotherapy, we designed this dose-finding study in an attempt to find the dose that can be safely added to radiotherapy and concurrent cisplatin in patients treated with transurethral resection for infiltrating bladder cancer. PATIENTS AND METHODS: After undergoing macroscopically complete transurethral resections for transitional carcinoma of the bladder, patients staged pT2 or higher and without distant metastases concurrently received 54 Gy of fractionated radiotherapy over 6 weeks with cisplatin (100 mg/m(2) q.3 w), starting on Day 1 of radiotherapy. Concomitant gemcitabine was administered on Days 1, 8, and 15 q.3 w for 2 cycles at a dose of 200 mg/m(2), escalated to 500 mg/m(2), with a 100 mg/m(2) increase at each dose level. The maximum tolerated dose was defined as the dose of gemcitabine associated with dose-limiting toxic effects (febrile neutropenia, Grade 4 thrombocytopenia, Grade 3 or 4 enteric toxicity, or Grade 4 nonhematologic toxicity) in 33% of the patients treated at that dose level. Six to 8 weeks after completing the therapy, the patients underwent cystoscopic reevaluation with multiple biopsies of the initial tumor site. RESULTS: Of our consecutive series of 16 patients, 5 received a gemcitabine dose of 200 mg/m(2)/week, 3 a dose of 300 mg/m(2)/week, 3 a dose of 400 mg/m(2)/week, and 5 a dose of 500 mg/m(2)/week for 6 weeks. No dose-limiting toxicity was observed at doses of up to 400 mg/m(2)/week. At the dose 500 mg/m(2)/week, 1 patient experienced an intestinal perforation that recovered after surgery, and another suddenly died after developing Grade 3 untreated diarrhea in the last treatment week. All of the 15 evaluable patients were microscopically disease free at the cystoscopic reevaluation; furthermore, the posttreatment computed tomography scans did not reveal any distant metastases. CONCLUSIONS: After transurethral resection for the conservative treatment of infiltrating bladder cancer, gemcitabine doses of up to 400 mg/m(2)/week seem to be safe in combination with cisplatin and radiotherapy in organ-sparing management. On the basis of the promising results of this Phase I study, we are currently conducting a Phase II trial to verify the possible improvement in local control resulting from the addition of gemcitabine.     

Gemcitabine and radiotherapy plus cisplatin after transurethral resection as conservative treatment for infiltrating bladder cancer: Long-term cumulative results of 2 prospective single-institution studies

BACKGROUND:

Cystectomy is the standard treatment for patients with infiltrating bladder cancer, but conservative treatment with cystoscopic resection followed by radiochemotherapy may be an alternative for highly selected patients. The addition of gemcitabine to cisplatin and radiotherapy may enhance disease control.

METHODS:

The long‐term clinical outcomes of 26 patients enrolled in a previously published dose‐finding study and a prematurely discontinued phase 2 trial were evaluated. All the patients underwent transurethral tumor resection followed by a radical dose of external radiotherapy administered at the same time as cisplatin and weekly gemcitabine therapy.

RESULTS:

After a median follow‐up of 74 months, the projected 5‐year clinical outcomes were a 70.1% overall survival rate, a 78.9% disease‐specific survival rate, and a 73.8% bladder‐intact survival rate.

CONCLUSIONS:

The long‐term follow‐up data from the current study confirmed that the addition of gemcitabine to radiotherapy and cisplatin is safe and leads to good local and distant disease control. The concomitant administration of cisplatin may explain the good long‐term organ preservation that was observed. Conducting confirmatory and comparative trials could satisfy an unmet need but requires the multidisciplinary cooperation of urologists in selecting the right patients for a bladder‐sparing strategy. Cancer 2011. © 2010 American Cancer Society.     

Neoadjuvant or definitive alternating chemotherapy and radiotherapy for infiltrating bladder cancer

Thirty-two patients with infiltrating bladder cancer were treated with transurethral resection followed by one course of alternating chemoradiotherapy before radical cystectomy (group A, 20 patients) or two courses as definitive procedure (group B, 12 patients). One course consisted of: cisplatin 20 mg/m2 i.v. and 5-fluorouracil 200 mg/m2 i.v. for 5 consecutive days, the first and the fourth weeks; radiotherapy 20 Gy in 10 fractions in the second and third weeks. At the seventh week the same integrated therapy was restarted in group B. All 32 patients were evaluable for toxicity after the first course: no grade IV toxicity was observed. Significant increase in hematological toxicity was observed in 12 patients who received the second course of chemoradiotherapy: two patients had grade IV toxicity, and five patients had grade III. Fifteen patients of group A underwent radical cystectomy: 40% had a pathological (p) complete response (CR) and 13.3% a partial response Five patients in group A did not receive either the second course of therapy or cystectomy because of age (three patients), vascular obliteration (one patient) and enteritis (one patient). Actuarial disease-free survival in group A is 78% at 21 months. All patients of group B obtained clinical (c) CR and all but one have no evidence of disease at a median follow-up of 10 months (range 6-13). The high pCR and cCR obtained in patients of group A and group B, respectively, appears promising. A longer follow-up and a larger number of patients is required to determine the role of this integrated treatment.     

Intra-operative radiotherapy with excision of urinary bladder carcinoma

From June, 1979 through Oct., 1986 forty patients (32 males and 8 females) with cancer of the urinary bladder have been treated by intraoperative radiotherapy (IORT) after surgical excision of their tumors. The five-year survival rate, by the Kaplan-Meier Method, was 100% in Grade I patients (n = 6), 56% in Grade II (n = 19), 49% in Grade III and 58% in all patients, respectively. Similarly, it was 62% for 33 patients in stages T1 and T2 of the disease and 42% for 7 patients graded T3 and T4 of only three patients out of eleven lost in this series, their deaths caused by urinary bladder cancer. IORT with a surgical excision of their bladder tumor provided excellent results in the control of recurrence.     

Hyperthermia as a treatment for bladder cancer

Modern cancer care is characterized by a focus on organ-sparing multi-modal treatments. In the case of non-muscle-invasive bladder cancer this is particularly true; treatment is focused on reducing the frequency of low-risk recurrences and preventing high-risk progression. Deep regional hyperthermia is an oncologic therapeutic modality that can help achieve these two goals. The combination of hyperthermia with chemotherapy and radiotherapy has improved patient outcomes in several tumor types. In this review, we highlight the biology of therapeutic fever-range hyperthermia, discuss how hyperthermia is administered and dosed, demonstrate how heat can be added to other treatment regimens, and summarize the data supporting the role of hyperthermia in the management of bladder cancer.     

Intra-operative electron beam radiotherapy and abdomino-pelvic surgery for cancer: influence on immunological parameters.

Evolution of some immunological parameters was observed during the first month in 20 patients with different abdomino-pelvic cancers who underwent surgery with intra-operative radiation therapy (IORT) (mean dose of 19.44 Gy, range 15, 25). Observed parameters before (DO-) and after procedure (DO+), on seventh (D7) and fourteenth (D14) days and fifth week (D30) were: lymphocyte count, lymphocyte subsets (CD19, CD3, CD4, CD8, CD56), natural killer (NK) activity, immunoglobulins, C3 and C4b fractions of complement, soluble receptor for interleukin 2 (sIL2-R). Results showed a decrease of circulating lymphocytes (DO-: 1189 +/- 168 cells/mm3; D7: 889 +/- 91; P = 0.011), of absolute number of CD3 lymphocytes (DO-: 785 +/- 114 cells/mm3; D7: 563 +/- 86; P = 0.025), of CD4 lymphocytes (DO-: 441 +/- 70 cells/mm3; DO+: 299 +/- 43; P = 0.013) and of CD8 lymphocytes (DO-:361 +/- 50 cells/mm3, D7:250 +/- 44; P = 0.006). All values returned towards preoperative levels by D30. Absolute number of NK cells was unchanged but NK activity was significantly diminished (effector target ratio 5:1 DO-:33 +/- 5%; DO+:44 +/- 7%; D7:18 +/- 3%; D14:21 +/- 4%; D30:25 +/- 4%). sIL2-R was significantly enhanced from D7 to D30. All these impairments are moderate and these observations provide some evidence of satisfactory tolerance to IORT for abdomino-pelvic cancers during the immediate postoperative period.     

Radical radiotherapy for urinary bladder cancer: treatment outcomes

The exact value of radiotherapy in the treatment of muscle-invasive bladder cancer is difficult to establish, as most studies exploring this issue are retrospective with different procedures for selecting patients for treatment, as well as varying treatment strategies. An estimate of the 5-year overall survival rate following radiotherapy is approximately 35% in consecutive-selected patients and approximately 25% in negative-selected patients.     

Pulmonary changes after radiotherapy for conservative treatment of breast cancer: a prospective study

PURPOSE: Radiotherapy (RT) after conservative surgery for breast cancer involves part of the pulmonary parenchyma with a potential detrimental effect of reducing the normal functional reserve. Such an effect deserves to be studied in depth, considering the given long life expectancy of these women. We prospectively analyzed high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) with correlation with dosimetric data from RT. METHODS AND MATERIALS: Lung HRCT and PFTs were performed in 41 women who had undergone conservative surgery for breast cancer before and 3 and 9 months after postoperative RT. The PFTs included forced vital capacity, forced expiratory volume in 1 s, total lung capacity, maximal expiratory flow at 50% and 25% of vital capacity, and the diffusion capacity of carbon monoxide. HRCT was matched with the RT treatment plan images to analyze the dosimetric correlation. RESULTS: At 3 months after RT, the lung alterations were classified at HRCT as follows: 46.3% were Grade 1, 24.4% Grade 2, and 7.3% Grade 3, and at 9 months, 58.5% were Grade 1, 19.5% Grade 2, and 0% Grade 3. The PFTs showed a significant decrease at 3 months, with only partial recovery at 9 months. Chemotherapy, but not hormonal therapy, was associated with PFT changes. The grade of fibrosis increased with increasing lung volume treated to a dose > or = 25 Gy. CONCLUSION: Lung changes, mainly related to damage to the alveolar-capillary barrier and smallest airway ramifications, were observed at 3 months, with only partial recovery at 9 months after RT. Minimizing the lung volume receiving > or = 25 Gy could reduce pulmonary toxicity.     

Local excision as conservative treatment for small rectal cancer

Twenty patients with small rectal cancer, characterized by a well differentiated tumour localized within 10 cm of the anal margin, and by penetration limited to the submucosa or to the muscular layer, were treated by local excision. Four of them, who presented with a deep tumour invasion in the rectal wall, also received adjuvant radiation therapy. Our experience proves the reliability of the selection criteria for patients who may benefit from this procedure. They all stand a fair chance of cure and the quality of their lives will improve because local tumour excision avoids anal sphincter resection. Two patients had local recurrences and had to undergo further curative local excision. The two who died from their tumours and who had distant metastases were unsuitable for both local resection and other therapeutic procedure. Finally, there was no postoperative morbidity.     

Split-course radiotherapy for urinary bladder cancer

In this retrospective study 119 patients with T1-T4 carcinoma of the urinary bladder were treated with split-course radiotherapy. The 3-week rest period was compensated with a 10% increase in the total radiation dose to 6600 cGy. Therapy was completed as planned by 86% of the patients. The actuarial 5-year survival for these patients was 20%. Both the 3- and 5-year survival figures were better for patients with local control of the tumour achieved either by combined surgery and radiotherapy or by radiotherapy alone, than for patients with recurrent tumours after radiotherapy. The results of the split-course regimen were comparable to the results of continuous radiotherapy used for urinary bladder cancer.     

Invasive bladder carcinoma: a pilot study of conservative treatment with accelerated radiotherapy and concomitant cisplatin.

From November 1992 to December 1997, 25 patients (inoperable or refusing cystectomy) were included in a prospective study to assess the feasibility, tolerance, and curative potential of accelerated radiotherapy (RT) and concomitant cisplatin. Median age was 74 years (range 49-86). Stage distribution was as follows: 1 T1, 10 T2, 8 T3, and 6 T4. Two patients had clinically positive pelvic nodes. The goal was to deliver a total dose of 40 Gy to the whole pelvis and bladder in 4 weeks using a concomitant boost of 20 Gy to the tumor or to the whole bladder during the third and fourth weeks (total dose 60 Gy), with daily cisplatin (6 mg/m(2)) before RT for patients with creatinine clearance > 50 ml/min. All but one patient completed the RT protocol. Daily cisplatin was successfully delivered in 18 patients. One patient presented with grade III ototoxicity. Diarrhea was scored grade III in two and grade IV in two patients. Acute urinary toxicity was scored grade III in one patient. Posttreatment late effects included bladder grade II and grade III in two patients and one patient, respectively; large bowel grade III in one; urethral grade III in one; and femoral head radionecrosis in one. Four-year overall and disease-specific survival rates were 23% and 35%, respectively. The latter was 60% for patients with T2 tumors. The 4-year actuarial locoregional control rate for all patients was 61%. In summary, accelerated RT and concomitant cisplatin is feasible with acceptable tolerance even in relatively old patients. Although outcome was better for patients with low-stage tumors, local control and survival rates appeared similar to those of standard RT schedules for a similar patient population.     

Intra-operative radiotherapy for carcinoma of the stomach

Intra-operative radiotherapy (IOR) was performed for the treatment of 101 patients with gastric cancer. Doses of 28 to 35 Gy with electron beams were delivered during the surgical procedure to tumour beds, high risk lymphnodes and/or remaining cancer nests after gastrectomy. Five-year survival rates were 87.2% for patients with Stage I disease, 83.5% for Stage II, 62.3% for Stage III and 14.7% for Stage IV. Compared with the data on 110 patients treated by surgery alone, IOR has yielded better results in patients with locally advanced disease. Based on these results, indications of IOR for gastric cancer were discussed.     

Adaptive radiotherapy for invasive bladder cancer: a feasibility study

PURPOSE: To evaluate the feasibility of adaptive radiotherapy (ART) in combination with a partial bladder irradiation. METHODS AND MATERIALS: Twenty-one patients with solitary T1-T4 N0M0 bladder cancer were treated to the bladder tumor + 2 cm margin planning target volume (PTV(CONV)). During the first treatment week, five daily computed tomography (CT) scans were made immediately before or after treatment. In the second week, a volume was constructed encompassing the gross tumor volumes (GTVs) on the planning scan and the five CT scans (GTV(ART)). The GTV(ART) was expanded with a 1 cm margin for the construction of a PTV(ART). Starting in the third week, patients were treated to PTV(ART). Repeat CT scans were used to evaluate treatment accuracy. RESULTS: On 5 of 91 repeat CT scans (5%), the GTV was not adequately covered by the PTV(ART). On treatment planning, there was only one scan in which the GTV was not adequately covered by the 95% isodose. On average, the treatment volumes were reduced by 40% when comparing PTV(ART) with PTV(CONV) (p < 0.0001). CONCLUSION: The adaptive strategy for bladder cancer is an effective way to deal with treatment errors caused by variations in bladder tumor position and leads to a substantial reduction in treatment volumes.     

Effectiveness of adjuvant radiotherapy in the conservative treatment of early breast cancer

Randomized study was made of 254 women with breast invasive duct cancer (pT1N0M0). In 61 patients, organ sparing operation was followed by radiation therapy of either breast alone or zones of regional metastasizing (57 patients) as well, with or without adjuvant chemotherapy or hormone therapy (tamoxifen). It was found that radiation of mammary gland, with or without additional radiation exposure of zones of regional metastasizing, results in both decrease recurrence development (p < 0.05) and significant (p < 0.05) increase in recurrence-free survival in women who had tumor size within the range from 1 to 2 cm in diameter in contrast to patients with tumor size not exceeding 1 cm, whose survival was not positively influenced by radiation.     

Influence of infiltrating lobular histology on local tumor control in breast cancer patients treated with conservative surgery and radiotherapy

To determine the influence of infiltrating lobular histology on local tumor control, the authors studied 49 patients with Stages I and II infiltrating lobular breast carcinoma treated by limited excision of the tumor and radiotherapy between 1968 and 1981 (median follow-up, 75 months). Results were compared with those in 561 cases of infiltrating ductal carcinoma similarly treated during the same period. The 5-year actuarial risk of local recurrence was similar for patients with infiltrating lobular or ductal carcinoma when the latter was evaluated as a single group (12% versus 11%). However, the 12% 5-year actuarial local recurrence risk for patients with infiltrating lobular carcinoma was intermediate between that for patients with infiltrating ductal carcinomas with an extensive intraductal component (23%) and those without an extensive intraductal component (5%). The pattern of recurrence in the breast was similar in the infiltrating lobular and ductal groups. All recurrences in patients with infiltrating lobular carcinoma and 80% of recurrences in the infiltrating ductal group occurred in the vicinity of the primary tumor (P = not significant). None of the clinical or morphologic features examined significantly influenced the risk of local recurrence in patients with infiltrating lobular carcinoma. The authors conclude that combined conservative surgery and radiotherapy appear to be a reasonable treatment option for patients with infiltrating lobular carcinoma, but further follow-up will be required to confirm these results.     

Capecitabine and radiotherapy as neoadjuvant treatment for rectal cancer

5-Fluorouracil (5-FU)-based neoadjuvant chemoradiotherapy is used in rectal cancer to prolong survival, downsize tumors prior to surgery, and allow for sphincter-sparing surgery. Capecitabine is an oral fluoropyrimidine that generates 5-FU preferentially within the tumor. It has been shown to be as effective as 5-FU and well tolerated in the metastatic and adjuvant settings in colorectal cancer. Capecitabine is more convenient for patients than 5-FU, and it avoids the risks of infection and thromboembolism associated with intravenous administration. It was also shown to reduce the use of medical resources, healthcare professionals' time, and cost of therapy. Emerging data from Phase II trials of neoadjuvant regimens in which capecitabine has been substituted for 5-FU are encouraging.     

Incidence of infiltrating cancer following superficial bladder carcinoma

Patients with histologically confirmed first diagnosis of superficial bladder carcinoma notified to the population-based cancer registry of the Swiss Canton of Vaud during the calendar period 1974-90 were actively followed-up to December 31, 1990 for the occurrence of a subsequent invasive tumour of the urinary bladder. Among 1,012 incident cases of superficial bladder neoplasms, followed for a total of 6,286 person/years at risk, 93 infiltrating tumours of the urinary bladder were diagnosed. Only 5.3 cases were expected on the basis of the general population of the canton. The overall standardized incidence ratio (SIR) was 17.5 (95% confidence interval, CI: 14.2–21.7). The SIR was significantly greater for females than for males. The SIR was highest between I and 4 years following registration of noninfiltrating cancer, and declined thereafter. The cumulative risk of invasive bladder cancer was 7%, 13%, and 16%, after 5, 10 and 15 years, respectively. This work provides population-based, accurate and reliable estimates of the risk of invasive bladder cancer following non-infiltrating cancers. Although the overall relative risk was almost 20-fold higher than in the general population, the cumulative risk of developing an invasive bladder cancer was only 16% at 15 years.     

The evolving role of chemotherapy for muscle infiltrating bladder cancer.

In order to improve survival in a disease where the majority of deaths occur from metastases, the integration of systemic chemotherapy is crucial. Research efforts must continue to focus on refining case selection criteria, improving complete response proportions, and overcoming drug resistance. The blanket recommendation of a single therapeutic strategy such as radical surgery, chemotherapy, or radiation therapy to all patients is quickly becoming an outdated approach. Refinements in the understanding of the clinical, pathologic, and molecular features of urothelial tumors will ultimately improve case selection. Evaluation of NM23 RNA levels, or DNA ploidy and T138 surface antigen expression, which have been shown to correlate with metastatic potential, may hold important therapeutic implications. The use of hematopoietic growth factors has the potential to improve both the tolerance of chemotherapy and complete response proportions, a prerequisite for cure. A recent report from Japan of granulocyte colony-stimulating factor with MVAC and other chemotherapy regimens for urothelial tumors corroborated an initial report in reducing the duration of neutropenia. However, the dose response curves for most of the known active agents are not well defined and, ultimately, new agents and strategies will be required. Gallium nitrate, when administered by continuous intravenous infusion, has significant single agent activity in cisplatin-refractory patients with 9/31 responses (29%), including 6 CRs (19%) and further studies are warranted. Drug resistance remains a major obstacle, and as the mechanisms are unravelled, more rational therapies can be designed. For example, resistance to Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) and vinblastine, two components in the MVAC regimen, are mediated in part by the MDR1 gene. Attempts are ongoing to identify prospectively those tumors with high levels of expression that may be more amenable to treatment with drugs that are not affected by this mechanism. The neoadjuvant approach allows an in vivo assessment of response to chemotherapy as well as the potential for bladder preservation. In most cases additional therapy directed at the primary is required as clinical understaging is a significant problem and pCR proportions are less than 30%. For some patients, initial surgery followed by treatment based on pathologic criteria may represent a better strategy. In these cases the recommendation for adjuvant treatment potentially limits therapy to a population of patients for whom therapy is essential. Based on available data, this would include patients with positive lymph nodes at the time of surgery. Ideally, patients with invasive bladder cancer should be entered into clinical trials designed to assess the impact of these strategies on survival.(ABSTRACT TRUNCATED AT 400 WORDS)