Superficial Bladder Cancer, Transitional Cell Carcinoma of Bladder
Conditions
Brief summary
Hypothesis: In selected patients external hyperthermia will be used in combination with intravesical Mitomycin-C (MMC) to treat recurrent transitional cell carcinoma (TCC) of the bladder after local resection and standard adjuvant therapy and thus prevent or delay recurrence and the need for radical cystectomy.
Detailed description
It is well established that tumor cells are sensitive to heat and when combined with a chemotherapeutic agent, drug uptake and intracellular distribution of drug within malignant cells is improved due to increased cellular permeability. Further, hyperthermia inhibits deoxyribonucleic acid (DNA) repair as a result of increased reaction between DNA and chemotherapy. By heating bladder tissue and accelerating the necessary series of reactions to link agents such as mitomycin C to cell DNA, this effect may be optimized. Depending on the extent of resection (and location, size, and depth of invasion of remaining tumor) after transurethral resection of the bladder tumor(TURBT), recommended adjuvant therapy consists of intravesical chemotherapy. MMC has been studied at doses as high as 80 mg without producing significant or irreversible side effects. The most commonly used dose of mitomycin is 40 mg.2 This pilot study proposes to use Mitomycin C at a dose of 40 mg in conjunction with deep hyperthermia to enhance the effect intravesical chemotherapy as second-line treatment of recurrent TCC (Stage Ta, T1, or Tis) of the bladder after surgical resection and standard adjuvant therapy.
Interventions
DEVICEHyperthermia System
Hyperthermia applied to heat the bladder to a temperature of 42 degrees Celsius for 40-60 minutes concurrent with mitomycin Treatment Schedule: 6 Weekly Sessions (Induction) followed by 4 Monthly Sessions (Maintenance) until documented second recurrence
DRUGMitomycin C
40 mg in 40 ml sterile water instilled into bladder
Sponsors
Mark Dewhirst
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Non-muscle invasive transitional cell carcinoma (TCC) of the bladder (Ta, T1, Tis) recurrent after initial surgery and at least one round of adjuvant treatment (i.e. 6 weeks of intravesical biological therapy with Bacillus Calmette Guerin (BCG) solution); or * An inability to tolerate BCG * Age \> 18 * Eastern Cooperative Oncology Group(ECOG) Performance Status 0-2 * Laboratory tests performed within 14 days of study enrollment: * Leukocytes ≥ 3,200, Absolute Neutrophil count ≥ 1,500, Platelets ≥ 100,000 * Hemoglobin ≥ 9.0 gm/dL, Total bilirubin ≤ institution upper limit of normal \*(ULN), Asparate Aminotransferase(AST) and Alanine Aminotransferase(ALT) ≤ 2.5 times ULN, Alkaline phosphatase ≤ 2.5 times ULN * Creatinine ≤ 1.5 times ULN * Women of child bearing potential must have a negative pregnancy test * If post-menopausal - Amenorrhea for ≥ 12 months
Exclusion criteria
* Pregnancy or breastfeeding * Muscle invasive disease (T2-T4) * Prior radiation to the pelvis * Peripheral neuropathy (any grade) * Thrombocytopenia, coagulation disorder or an increase in bleeding tendency due to other causes * Known bladder fistula * Hypersensitive or idiosyncratic reaction to mitomycin-C or its components in the past
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability | During Treatment Phase average 6 weeks | Number of patient treatments stopped due to safety concerns or treatment intolerability. All events below are grade 1/2 toxicity. No grade 3-5 toxicity was observed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Recurrence Free-survival | Median follow-up 3.18 years | Time to first recurrence of cancer in the bladder. |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: 09/2008-09/2010 Location: Urology and Radiation Oncology Clinics
Participants by arm
| Arm | Count |
|---|---|
| Mitomycin C With Hyperthermia Mitomycin C and Hyperthermia | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Mitomycin C With Hyperthermia |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 14 / 15 |
| serious Total, serious adverse events | 0 / 15 |
Outcome results
Primary
Safety and Tolerability
Number of patient treatments stopped due to safety concerns or treatment intolerability. All events below are grade 1/2 toxicity. No grade 3-5 toxicity was observed.
Time frame: During Treatment Phase average 6 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Abdominal pain | 5 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Fatigue | 2 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Myalgia | 1 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Heat intolerance | 1 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Urethral pain | 6 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Chemical cystitis | 4 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Hematuria | 3 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Bladder spasm | 2 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Weak urinary stream | 1 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Vaginitis | 1 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Nausea | 2 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Constipation | 1 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Swelling | 4 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Pruritis | 3 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Rash | 2 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Bruising | 1 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Flushing | 1 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Dizziness | 2 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Confusion | 1 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Anxiety | 1 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Extrapyramidal symptoms | 1 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Urinary Tract Infection | 2 Grade 1/2 event count (no grade 3+) |
| Hyperthermia System, Mitomycin C | Safety and Tolerability | Hypertension | 3 Grade 1/2 event count (no grade 3+) |
Secondary
Median Recurrence Free-survival
Time to first recurrence of cancer in the bladder.
Time frame: Median follow-up 3.18 years
Population: Entire cohort
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hyperthermia System, Mitomycin C | Median Recurrence Free-survival | 15.4 Months |