A Randomized Phase II Study Of Reirradiation And Hyperthermia Versus Reirradiation And Hyperthermia Plus Chemotherapy For Locally Recurrent Breast Cancer In Previously Irradiated Area

Patients with a local regional recurrence of invasive breast cancer in
previously irradiated area treated with standard therapy consisting of
radiotherapy and hyperthermia have a 3 year local control rate of 40 %.
In patients with inoperable local regional recurrences of breast cancer in
previously irradiated areas subsequent local control is difficult to maintain
with reirradiation only or combined with chemotherapy or hyperthermia.
Effective treatment options are limited and as a consequence there is a high
risk on subsequent failure and uncontrollable local disease. Moreover,
progression of local regional recurrences may ultimately cause ulceration with
odor, pain and bleeding resulting in considerable physical and mental suffering
In view of the known radio enhancing effect of Cisplatin and the enhancement of
Cisplatin and radiation effect by hyperthermia one might hypothesize that the
combination of radiotherapy, hyperthermia and cisplatin can lead to improvement
of local control, though toxicity may also be enhanced. Our department has
experience with this trimodality treatment in esophageal cancer and uterine
cervix cancer where it appears feasible. In the treatment of cervix cancer 40
mg/ m2 CDDP once a week during radiotherapy is used currently.
It seems worthwhile to evaluate the feasibility and efficacy of the combination
of re-irradiation, hyperthermia and weekly Cisplatin for local regional
recurrent breast cancer in previously irradiated area. See also chapter 1 of
the protocol.

Primary objective phase II:

To explore if there is an indication of a positive effect on local control rate
of adding Cisplatin to local reirradiation and hyperthermia to patients with
local regional recurrent breast cancer in previously irradiated area

Secondary objectives phase II:

* To describe the effect of adding Cisplatin to the standard treatment on acute
toxicity
* To describe the effect of adding Cisplatin to the standard treatment on
clinical complete response rate
* To explore the effect of adding Cisplatin to the standard treatment on time
to disease progression local, regional or distant
* To explore the effect of adding Cisplatin to the standard treatment on time
to death by any cause
* To describe the effect of adding Cisplatin to the standard treatment on late
toxicity

A two-arm non-blinded prospective randomized phase II trial which will be
performed in a single centre focusing on local control rate clinically assessed
according to the RECIST criteria. Patients will be randomised in a 1:1 ratio.
The study has early stopping rules in the study arm for excessive toxicity and
lack of feasibility.
Patients will be randomized before treatment to receive 8 x 4 Gy to the
affected area, two fractions per week, in combination with once weekly
hyperthermia (standard treatment) or the same treatment combined with Cispatin
40 mg/m² once per week. Cisplatin is given intravenously during the
hyperthermia session. The first treatment session is always followed by
hyperthermia, see schedule below. For simulation procedures PET-CT is used, see
section 6 and 9.
The overall treatment time in both arms is 4 weeks. Patients will be stratified
by size of recurrence more than 5 cm or less than or equal to 5 cm and
time-interval between primary breast cancer and first recurrence more than 3
years or less than or equal to 3 years. Safety in terms of unacceptable
toxicity (grade 4 dermatitis: necrosis/ulceration induced by treatment) and
feasibility will be monitored in the study arm using a Simon two stage minimax
design.

For the experimental arm: Cisplatin 40 mg/m² once per week, given intavenously.

Translational study on PET-CT: minimum of 1 extra PET-CT scan, maximum of 5
extra PET-CT scans, only if the patient gives consent for this study!

Translational study on tumour biology: DNA Damage response and hypoxia: 2 x
subcutaneous injection with Lidocaïne 2 %; 2 x biopsy of the tumour; 2 x
maesurement of hypoxia with the Eppendorf electrode, only if the patient gives
consent for this study!

possible higher risk grade 4 dermatitis (ulceration/ necrosis), specific
stopping rules are applied

Cisplatin side effects: nausea, anemia, negative effect on immune system

5 x plasma sample (if in Cisplatin-arm)

Translational study on PET-CT: minimum of 1 extra PET-CT scan, maximum of 5
extra PET-CT scans, only if the patient gives consent for this study!

Translational study on tumour biology: DNA Damage response and hypoxia: 2 x
subcutaneous injection with Lidocaïne 2 %; 2 x biopsy of the tumour; 2 x
maesurement of hypoxia with the Eppendorf electrode, 2 x plasma sample, only if
the patient gives consent for this study!