RTOG 95-07
PHASE I STUDY OF TOPOTECAN PLUS CRANIAL RADIATION FOR GLIOBLASTOMA MULTIFORME
| Medical Oncology | David Macdonald, M.D.
(519)685-8640 FAX # (519) 685-8624 |
| Radiation Oncology | Barbara Fisher, M.D. (519) 685-8650 FAX # (519) 685-8627 |
| Activation Date: CLOSURE DATE: Current Edition | October 13, 1995 December 25, 1996 October 25, 1996 |
RTOG 95-07
PHASE I STUDY OF TOPOTECAN PLUS CRANIAL RADIATION FOR GLIOBLASTOMA MULTIFORME
SCHEMA
| R E G I S T E R | Topotecan 00.5 mg/m2 per day i.v. given five times per week q3 weeks x maximum 3 courses* (first ten patients), opened: 10/13/95; closed: 1/4/96 |
| then escalate to 1.0 mg/m2 per day x 5 days q3 weeks x maximum 3 courses* (second ten patients), opened: 5/1/96; closed: 6/14/96 | |
| then escalate to 1.5 mg/m2 per day x 5 days q3 weeks x maximum 3 courses*, opened: 10/25/96 | |
| Cycle 1: radiation treatment days 1-5 (protocol days 1-5) Cycle 2: radiation treatment days 16-20 (protocol days 22-26) Cycle 3: protocol days 43-47 |
| Radiation Therapy Treatment Volume 60 Gy/30 fractions/6 weeks (2 Gy fractions once a day five days a week) | |
| Total RT | 60 Gy |
| Initial Field** | 46 Gy |
| Boost Field*** | 14 Gy |
| Fraction Size | 2 Gy |
| * Unless there is disease progression ** For the first 46 Gy/23 fractions, the treatment volume should include the volume of contrast-enhancing lesion and surrounding edema on preoperative CT/MRI scan plus a 2.0 cm margin. *** After 46 Gy, the tumor volume should include the contrast-enhancing lesion (without edema) on the presurgery CT/MRI scan plus a 2.5 cm margin. | |
Eligibility: (See Section 3.0 for details)
- Histology-confirmed glioblastoma multiforme
- Tumor supratentorial in location
- Therapy begins within five weeks of surgery (but within one week after registration)
- No prior chemotherapy, radiotherapy to the head and neck, or radiosensitizer
- Age >=18 years
- Karnofsky Performance Status >=50%
- Neurologic functional status 0, 1, or 2
- Hemoglobin >=10 g/dL, absolute neutrophil count >=1500/mm3, platelets >=100,000/mm3
- BUN <=25 mg/dL and creatinine <=1.5 mg/dL
- Bilirubin <=1.5 mg/dL and SGPT or SGOT <= twice normal range
- Normal chest x-ray
- Signed study-specific informed consent
Required Sample Size: maximum 45
6/3/96
10/25/96
RTOG 95-07
ELIGIBILITY CHECK (1/31/96)
Case # ________________
________________(Y) 1.
Histologically confirmed glioblastoma mutiforme or gliosarcoma?
________________(Y) 2.
Diagnosis made by surgical biopsy or excision?
________________(Y) 3.
Is tumor supratentorial in location?
________________(Y) 4.
Will therapy begin within 5 weeks of surgery?
________________(N) 5.
Has patient received prior radiotherapy to head and neck, chemotherapy
or radiosensitizer?
________________(>=
18) 6. What is the age of the patient?
________________(>=
50) 7. What is the Karnofsky Performance Status?
________________(0-2)
8. What is the Neurological Function Status?
________________(>=
10) 9. What is the hemoglobin?
________________(>=
1.5) 10. What is the absolute neutrophil count (x 1000)?
________________(>=
100) 11. What is the platelet count?
________________(<=
25) 12. What is the BUN?
________________(<=
1.5) 13. What is the creatinine?
________________(<=
1.5) 14. What is the bilirubin?
________________(Y) 15.
Is the SGOT or SGPT &;lt;= twice your institution's normal
range?
________________(Y) 16.
Has a diagnostic CT or MRI with and without contrast been performed
pre-operatively?
________________(Y/N)
17. Has the same scan with and without contrast been performed
post operatively? ________________(Y) If no, did the patient
have only a stereotactic needle biopsy?
________________(Y) 18.
Has a study-specific consent been signed?
________________(Y) 19.
Has the patient's steroid dose been stable for the past seven
days?
________________(M/F)
20. What is the patient's gender? (if male, skip to Q23)
________________(N/Y)
21. Does she have child-bearing potential? (if no, skip to
Q23)
________________(Y) 22.
Has she tested negative for pregnancy?
________________(Y/N)
23. Is the patient sexually active?
________________(Y) If yes, has patient
been counseled about practicing contraception while undergoing
treatment and for 3 months after completing treatment?
________________(N) 24.
Is the tumor multifocal?
________________(N) 25.
Is the tumor recurrent?
________________(N) 26.
Does the patient have AIDS?
________________ Patient's Name
________________ Verifying Physician
________________ Patient ID #
________________ Referring Institution # if different
________________ Birthdate
________________ Sex
________________ Race
________________ Social Security Number
________________ Zip Code (9 digit if available)
________________ Method of Payment
________________ Treatment Start Date (must be after registration)
________________ Treatment
Assignment
Completed by __________________________________Date
_______________
1.1 Chemotherapy of Brain Tumors
Presently the nitrosoureas are the main chemotherapy
for malignant astrocytomas. Most often they have been used in
a "pseudo-adjuvant" setting in conjunction with or immediately
following radiation treatment. Although it is generally believed
that they can effectively increase the duration of survival, these
effects tend to be quite modest.1-3
Other agents that may have some activity include procarbazine,
vincristine, 5-fluorouracil, VP-16, VM-26, dianhydrogalactitol,
cisplatin, and AZQ.3-5
However, these drugs rarely produce significant numbers of complete
or durable responses.
A second problem in the chemotherapy of brain
tumors is that although the nitrosoureas are the mainstay of therapy,
because of their ability to cause delayed and cumulative myelosuppression,
they can be delivered only at infrequent intervals (ie.
every 6-8 weeks). In theory this may limit the degree of primary
tumor control if long drug-free periods occur. Agents producing
less myelosuppression which can be given more frequently may help
to alleviate this problem.
A third major problem is that of tumor heterogeneity.
Malignant gliomas have great heterogeneity with respect to various
morphologic features6
and with respect to sensitivity to chemotherapeutic agents.7,8
Therefore single drug treatment is likely to be relatively ineffective
for producing long-term tumor control. However, identification
of more active agents may make effective combination chemotherapy
of brain tumors a more realistic goal.
A final problem with chemotherapy of brain tumors
is adequate delivery of active drugs to the tumor. This is important
if a significant dose-response relationship is present. Although
many investigators feel that drugs that cross the blood-brain
barrier are most effective against intracranial tumors, there
is some controversy about its importance in the treatment of primary
brain tumors.9,10
Several studies utilizing intracarotid artery mannitol infusions
followed by drugs have shown some promise in allowing drugs to
pass through the blood-brain barrier.11-12
Intracarotid artery infusion of drugs alone has also been attempted
to increase the local concentration of drug in the blood infusing
the tumor region with some success.13,14
Interstitial delivery of chemotherapy directly within brain tumors
and high-dose systemic chemotherapy with autologous bone marrow
or peripheral progenitor cell rescue have also been proposed to
overcome the drug delivery issue.15,16
However, these techniques are technically difficult to perform,
have potentially significant morbidities attached to them, and
have not yet demonstrated superiority over conventional treatment.
1.2 Topotecan: Mechanism of Action
Camptothecin and its analogues, including topotecan,
are believed to exert cytotoxic effects through the inhibition
of topoisomerase I.17,18
This is the only known class of drugs which exhibits this mechanism
of action. However, inhibition of topoisomerase activity is not
an unknown mechanism of action since many classes of drugs (eg.
epipodophyllotoxins) operate through inhibition of topoisomerase
II (topo II).
Topoisomerases are enzymes which break strands
of DNA so that the strands can be rotated around each other and
then the break resealed. They can be divided into two classes
according to the nature of the mechanisms of action they employ.19
Type I topoisomerase is a monomeric protein of
about 100 Kilodaltons (KDa). It is capable of making
a transient break in a single strand of the DNA helix. This reduces
the torsional strain on the DNA and allows the DNA to unwind ahead
of the replication fork. This enzyme is capable of relaxing highly
negatively supercoiled DNA. In the eukaryotic version of this
enzyme, a phosphotyrosyl bond is formed between the enzyme and
the 3' end of the DNA break. In this process there is a transfer
of a phosphodiester bond in the DNA to the protein. The structure
of the DNA is manipulated and the DNA is rejoined. Since the
reaction requires only the transfer of bonds, not irreversible
hydrolysis, no input of energy is required. Topo I is believed
to function in DNA replication, RNA transcription, genetic recombination,
chromosomal condensation/decondensation and in viral encapsulation.
Its presence is not cell-cycle dependent and it is found in quiescent
as well as proliferating cells. It appears, however, that this
enzyme is not required for the viability of cells. Topo II seems
to fulfil the functions of topo I when it is absent. Double mutants,
which lack both topo I and II have defects of replication and
transcription.19
Cells lacking the topo I enzyme are resistant
to camptothecin, while cells containing higher topo I levels are
hypersensitive to these drugs. The camptothecins seem to block
the rejoining step of the breakage-reunion reaction of the enzyme,
leaving the enzyme covalently bound to DNA.19,20
This results in protein associated single strand breaks in the
DNA.
1.3 Experimental Antitumor Activity
Topotecan demonstrated good antitumor activity
(increased life spans (ILS) > 95%) in several intraperitoneally
(IP) and intravenously (IV) implanted murine tumor
systems, including P388 leukemia, L1210 leukemia, B16 melanoma,
Lewis lung carcinoma and M5076 reticulum cell sarcoma.18-21
Topotecan was equally effective when administered IP or IV against
IP or IV implanted tumors. Subcutaneous administration did not
result in any local tissue damage. This drug was also equally
effective when administered enterally or parenterally in some
tumors, suggesting that, in mice, the bioavailability is high.
The antitumor activity of topotecan in tumor-bearing
mice can be enhanced by using an intermittent dosing regimen.
Results were dependent upon how sensitive the tumor model was
to bolus treatment with topotecan. In studies in which topotecan
was administered every three hours for 4 doses, a broader therapeutic
dose range was noted in tumors that were quite sensitive to bolus
therapy, including IV-implanted L1210 leukemia, IP M5076 reticulum
sarcoma, SC colon 51, and SC B16 melanoma. In tumor types that
were less sensitive to bolus therapy, such as SC implanted colon
26 and Madison 109 lung carcinomas, the divided dose resulted
in a greater degree of inhibition at the MTD.18
The activity of topotecan has also been investigated
using a human tumor clonogenic assay.22
Fifty-five human tumor specimens were exposed to topotecan for
one hour at a concentration of either 1 of 10 µg/ml or as
a continuous exposure (0.1 or 1.0 µg/ml). At a
concentration of 0.1 µg/ml of continuous exposure, response
rates of 29, 27, and 37% were seen against breast, nonsmall cell
lung, and ovarian cancers, respectively, Activity was also seen
against stomach, colon, and renal cancer, and mesothelioma. Incomplete
cross-resistance was noted with doxorubicin, 5-FU and cyclophosphamide.
1.4 Animal Toxicity
Preclinical toxicology testing has been performed
in BDF1 mice, Sprague-Dawley rats and beagle dogs.18
The single dose LD10
in mice was 75 mg/m2.
This compound demonstrates strong cumulative toxicity since the
five daily dose LD10 in mice was 14 mg/m2/d.
In a single dose toxicity study, rats given 147.5 mg/m2
experienced dose-related toxicity to proliferating tissues of
the gastrointestinal tract, bone marrow, and lymphoid tissues.
Toxicity was reversible in surviving rats. Lethality occurred
in 3/12 rats on days 5-6 of the study. Toxicity at 7.49 mg/m2
(0.1 x MELD10) was mild
and reversible. Rats administered 13.8 mg/m2
daily for five days experienced dose-related toxicity to the same
proliferating tissues as mice who received 147.5 mg/m2
on the single dose study. The testis and liver were also affected.
Death occurred in 5/12 rats on days 7-8 of the study.
Single and five daily dose toxicity studies were
also performed in beagle dogs. Lethality was seen at the MELD10
(74 mg/m2,
3/10 dogs) and at 1.5 x MELD10
(120 mg/m2,
6/10 dogs) in the single dose study and
at 1/3 MELD10 (4 mg/m2,
1/10 dogs) in the five daily dose study. Clinical signs of GI
toxicity and marrow toxicity were seen, as well as increased BUN.
Histopathic lesions were similar to those found in the rats including
lymphoid, gastrointestinal, marrow and ovarian toxicity. Liver
and spleen toxicity was seen in the single dose study and testicular
atrophy was observed in the five daily dose study. Based on the
results of these studies, 1/30 MELD10
was chosen for the starting dose in humans.
1.5 Human Phase I Trials
Topotecan has been studied in several schedules
in phase I studies in the United States and Europe.
Three phase I studies have been carried out in
which topotecan was administered as a 30 minute infusion daily
x 5 days every 3 weeks.23-25
In all three trials myelosuppression, principally neutropenia
was dose limiting. Nadir neutrophil counts occurred on day 8-11
and were of brief duration. The recommended phase II dose from
all three studies was the same: 1.5 mg/m2/day
x 5 days every 3 weeks.
Other toxic effects seen during these trials
were as follows:
° mild-moderate nausea/vomiting (infrequent)
No serious non-hematologic toxicity has been
documented.
In the phase I trials several patients have experienced
objective tumor regression as follows:
Ovary: 1 partial response
Nonsmall cell lung cancer: 1 complete response, 3 partial responses
Small cell lung cancer: 1 partial response
Esophagus: 1 partial response
"Minor" responses have been noted in
several other tumor types. Given that most patients on phase
I trials are heavily pretreated and receive what is later known
to be subtherapeutic dosing, this list of documented responses
is extremely encouraging.
1.6 Pharmacokinetic Studies
Pharmacokinetic studies of topotecan in humans
were performed as part of the Phase I trial at JHOC (T89-0165)
.24
Twelve patients received a dose of 0.5-1.5 mg/m2
topotecan daily x 5. The harmonic half-lives were 3.3 and 80 minutes.
The renal and plasma clearance rates were 446 ± 55 and 630
± 106 ml/min/m2,
respectively. The volume of distribution (Vd) was 20.7
± 4.7 L/m2
on day 1, but increased to 40.3 ± 5.9 L/m2
by day 5.
Pharmacokinetics were also performed at Memorial
Sloan Kettering as part of a Phase I study (T90-0003).23
Six patients received a dose of 1.5 mg/m2.
The median alpha and beta half-lives were 9.0 and 103 minutes,
respectively. The clearance was 2080 mL/min/m2,
and the Vd was 186 L/m2.
The optimal dose and schedule selected for phase
II trials based on the results of these trials, is 1.5 mg/m2
IV daily x 5 every 3 weeks.
1.7 Topotecan and Radiation
Topotecan may be a radiation sensitizer by preventing
DNA repair and modifying radiation-induced DNA lesions. Topoisomerase
I inhibitors can enhance radiation damage by preventing DNA repair
and survival recovery in human neoplastic cells. Boothman et
al reported that post-treatment exposure to camptothecin, a specific
inhibitor of topoisomerase I, enhanced the lethal effects of radiation
on radioresistant human malignant melanoma cells in vitro
.26
Mattern et al reported potentiation of radiation-induced
cell killing by topotecan in Chinese hamster ovary or P388 murine
leukemia cells in vitro.27
The potentiation of radiation toxicity by topotecan required
the presence of the topoisomerase I inhibitor during the first
few minutes post-irradiation. Kim et al found potentiation of
radiation response in human carcinoma cells in vitro
and murine fibrosarcoma (in isogenic BALB/c mice) in
vivo by topotecan.28
The radiosensitization effect was dependent upon drug dose and
on the time sequence of topotecan and radiation. The in
vivo studies showed best potentiation when topotecan was administered
2 or 4 hours before radiation. Administration of the drug 2 hours
after radiation did not produce any significant potentiation of
radiation. There was no disproportionate enhanced radiation skin
reaction in the mice exposed to combined topotecan and radiation.
Boscia et al reported radiation sensitization by topotecan in
a human squamous carcinoma cell line (SCC-25) resistant
to cisplatin in vitro and in the FSaIIC fibrosarcoma cell
line growing in C3H mice in vivo .29
Various reports indicate a dose enhancement ratio of 2.0 or more.
The mechanism of topotecan radiosensitization is speculated to
be that topotecan inhibition of topoisomerase I prevents potentially
lethal DNA damage repair leading to a conversion of repairable
non-lethal DNA lesions induced by radiation into irreparable topoisomerase
I bound lethal double strand breaks. The radiosensitization action
of topotecan occurs at drug concentrations achievable in
vivo without excessive toxicity.
Phase I and phase II studies of radiosensitization
of topotecan in human tumors are underway, using a variety of
topotecan and radiation dose/schedules. No results are available
at this time.
1.8 Topotecan
and Gliomas
Topotecan has demonstrated activity against a
variety of pediatric and adult central nervous system tumor xenografts
growing subcutaneously and intracranially in athymic nude mice.
Significant tumor regressions and growth delays were reported
by Friedman et al against xenografts derived from ependymomas,
childhood high grade gliomas, adult high grade gliomas, and medulloblastomas.30
Blaney et al. examined the plasma and cerebrospinal fluid pharmacokinetics
of topotecan in non-human primates.31
Peak CSF concentrations of topotecan occurred 30 minutes following
intravenous drug administration. The CSF disappearance parallelled
that of plasma. The mean ratio of the area under the CSF concentration-time
curve to that in plasma was 0.32 (range, 0.29-0.37).
Thus topotecan can penetrate CSF in potentially therapeutic concentrations,
indicating reasonable penetration of the blood-brain barrier.
The combination of activity against human primary brain tumor
xenografts in vivo and good CSF penetration makes topotecan
a good candidate for further study in patients with CNS tumors.
A phase I study of topotecan in pediatric patients
with malignant solid tumors reported stable disease in one patient
with astrocytoma and another with medulloblastoma but progressive
disease in one patient with glioblastoma.32
In this study topotecan 0.75-1.9 mg/m2
by continuous intravenous infusion daily for 3 days was given.
The recommended pediatric phase II topotecan dose was 1.0 mg/m2/day
for 3 days as a constant intravenous infusion followed by G-CSF
support, with cycles repeated every 21 days. The actual doses
administered to the 3 patients with primary brain tumors are unknown.
There was minimal nonmyelosuppressive toxicity. Myelosuppression
was dose limiting, both neutropenia and thrombocytopenia.
The National Cancer Institute of Canada Clinical
Trials Group (NCIC-CTG) has recently completed a phase II trial
of topotecan in recurrent malignant glioma in adults.33
Topotecan 1.5 mg/m2
intravenously daily for 3 days, repeated every 3 weeks, was used.
There were 2 objective responses (1 complete response for
9 days until death from neutropenic sepsis, and 1 partial response
ongoing at 24+ months), 21 patients with stable disease, and
8 with progressive disease. The overall median progression-free
survival was 3.3 months and median survival 6.6 months. Toxicity
was primarily myelosuppression severe but brief, neutropenia was
common. The median granulocyte nadir was 0.3 x 109/L
and 25 of 31 patients experienced grade 3 or 4 neutropenia (<
1.0 x 109/L).
Only 9 patients experienced grade 3 or 4 thrombocytopenia and
1 patient had grade 3 anemia. Despite this, infection was uncommon
(4 of 31 patients), and only 12 of 109 cycles administered
were given at reduced dose due to prior toxicity. Nonhematologic
toxicity was uncommon. In particular, there was no excessive
skin reaction in prior radiated areas on the scalp and no recognized
neurologic toxicity (such as leukoencephalopathy) to suggest
that topotecan chemotherapy increased the toxicity of prior radiation
therapy. All patients had received prior radiation. The degree
of hematologic toxicity may have been slightly greater in those
who had received prior chemotherapy (mainly nitrosoureas)
than in chemotherapy naive patients. Although the objective response
rate (6.5%) was low, 68% had stable disease suggesting
that topotecan has perhaps some activity in malignant glioma.
This combined with the tolerable toxicity suggests that further
investigation, either in different dose schedules, or as a radiation
sensitizer, is warranted.
2.1 To determine the maximum
tolerated dose (MTD) and dose limiting toxicity (DLT)
of combined topotecan and cranial radiation therapy.
2.2 To determine that
acute and delayed treatment-related toxicity is acceptable with
this study regimen.
3.1 Eligibility Criteria
3.1.1 Histologically confirmed
glioblastoma multiforme; gliosarcomas are also eligible.
3.1.2 Diagnosis must be
made by surgical biopsy or excision.
3.1.3 The tumor must be
supratentorial in location.
3.1.4 Therapy must begin
within five weeks of surgery.
3.1.5 Patients must not
have received prior radiotherapy to the head and neck, chemotherapy,
or radiosensitizer therapy.
3.1.6 Age >=18 years.
3.1.7 Karnofsky Performance
Status >=50% (Appendix II)
3.1.8 Neurological Functional
Status 0,1, or 2 (Appendix II)
3.1.9 Adequate bone marrow
reserve (hemoglobin >=10 g/dL, absolute neutrophil count
>=1500/mm3,
platelets >=100,000/mm3)
and normal renal (BUN <=25 mg/dL and creatinine <=1.5
mg%) and hepatic (bilirubin <=1.5 mg% and SGPT or
SGOT <=twice normal range) function. All
mandatory studies specified in Section 4.1 must have been performed.
3.1.10 A diagnostic CT
scan (or MRI) with and without contrast must be performed
preoperatively and postoperatively prior to the initiation
of radiotherapy.
3.1.10.1 A post-operative
scan is not required if the extent of surgery was a stereotactic
biopsy.
3.1.11 Patients must have
signed a study-specific informed consent. If the patient's mental
status precludes his/her giving informed consent, written informed
consent may be given by the patient's legal representative.
3.1.12 Women with child-bearing
potential must have a negative pregnancy test (or other definitive
evidence of no pregnancy) and all sexually active patients
must practice contraception while undergoing treatment and for
three months post treatment.
3.1.13 Steroid dose must
be stable for one week prior to entry.
3.2 Ineligibility Criteria
3.2.1 Well differentiated
or anaplastic astrocytoma.
3.2.2 Multifocal glioma.
3.2.3 Recurrent glioblastoma
multiforme.
3.2.4 Patients with prior
malignancies, except carcinoma in situ of the cervix or
nonmelanomatous skin cancer, unless disease free >=3 years.
3.2.5 Major medical illness(es)
or psychiatric impairment(s) that will prevent completion
of protocol therapy or would interfere with follow-up.
3.2.6 Inability to obtain
histologic proof of glioblastoma.
3.2.7 Patients with acquired
immune deficiency syndrome (AIDS).
3.2.8 Inability to meet
eligibility requirements in Section 3.1.
4.1 Mandatory Studies
4.1.1 Complete medical
history and general physical examination (to include vital
signs).
4.1.2 CT or MRI scan with
and without contrast performed preoperative and postoperatively
prior to the initiation of radiotherapy (mandatory for eligibility);
same type of scan must be used both preoperatively and postoperatively.
4.1.3 CBC with differential,
platelet count, blood chemistries (SMA 12).
4.1.4 Detailed neurological
examination (to include mini mental status evaluation)
immediately prior to beginning protocol treatment course.
4.1.5 Chest x-ray.
4.2 Additional Studies
4.2.1 Additional renal
or liver function tests as indicated.
5.1 Patients can be registered
only after pretreatment evaluation is completed and eligibility
criteria are met. Patients are registered prior to any
protocol therapy by calling RTOG headquarters at (215) 574-3191,
Monday through Friday 8:30 a.m. to 5:00 p.m. ET. The patient will
be registered and a case number will be assigned and confirmed
by mail.
The following information must be provided:
5.2 Institutions with
IRB approval for RTOG 94-17 (limited participation study)
must enter eligible patients to that study until it meets accrual
requirements.
6.1 General Requirements
6.1.1 Treatment will be
delivered with megavoltage photon beam machines of energy >=4
MeV. Electron, particle, or implant boost is not permissible.
6.1.2 The patient may
be treated in the supine or other appropriate position. A head-holding
device that is transparent to x-rays must ensure adequate immobilization
during therapy and ensure reproducibility. The treatment volume
for both the initial volume and the conedown volume will be based
on the preoperative CT/MRI.
6.1.2.1 The initial treatment
volume will include the contrast-enhancing lesion and surrounding
edema (if it exists) demonstrated on CT/MRI plus a 2.0
cm margin. If no surrounding edema is present, the initial treatment
volume should include the contrast-enhancing lesion plus a 2.5
cm margin.
6.1.2.2 For the first
46 Gy/23 fractions, the treatment volume should include the volume
of contrast-enhancing lesion and surrounding edema on preoperative
CT/MRI scan plus a 2.0 cm margin. After 46 Gy, the treatment volume
should include the contrast-enhancing lesion (without edema)
on the presurgery CT/MRI scan plus a 2.5 cm margin.
6.1.3 Treatment plans
may include opposed lateral fields, a wedge pair of fields, or
multiple field techniques. CT or MRI-guided treatment planning
is necessary to assure accuracy in the selection of field
arrangements. Inability to achieve field placement as defined
by the protocol will result in variation scores at RTOG Headquarters
review. Isodose distributions for the initial target volume and
the conedown target volume are required on all patients, including
those treated with parallel opposed fields. A composite plan is
required showing the dose distribution to the initial treatment
volume and the boost treatment volume. The inhomogeneity in dose
across the target volume will be kept to a minimum. The minimum
and maximum doses to the treatment volume should be ± 5%
of the dose at the center of the volume. The maximum dose should
be to a cross-sectional area <= 2 cm2.
The use of vertex fields require either a
diagram or photograph of treatment position to be submitted to
RTOG headquarters. There must be at least two shaped treatment
fields with each field treated daily. Treatment with a single
beam is not acceptable. Port films of each field will be taken
weekly.
6.2 Dose Definition and Schedule
RT must begin within one week of registration. Treatment
will be given in 2 Gy fractions once daily. All treatment volumes
will be based on preoperative CT/MRI. The initial 46 Gy in 23
fractions (2 Gy/fraction) will be delivered to the initial
treatment volume. The final 14 Gy in 7 fractions will be delivered
to the boost treatment volume. All portals will be treated during
each treatment session. Doses are specified as the treatment
dose which will be to the center of the treatment volume. For
the following portal arrangements, the target dose will be specified
as follows:
6.2.1 For two opposed
coaxial equally weighted beams: on the central ray at mid-separation
of beams.
6.2.2 For an arrangement
of two or more intersecting beams: at the intersection of the
central ray of the beams.
6.2.3 For complete rotation
or arc therapy: in the plane of rotation at the center of rotation.
6.2.4 Treatment with a
single beam is not acceptable due to unacceptable tumor dose inhomogeneity.
6.2.5 The technique of
using two opposing co-axial, unequally-weighted fields is not
recommended due to unacceptable hot spots and unacceptable tissue
inhomogeneity. However, if this technique is utilized, the dose
will be specified at the center of the treatment area.
6.2.6 Other or complex
treatment arrangements: at the center of the target area.
6.3 Dose Limitation to Critical Structures
The lens and cervical spine must be shielded from
the direct beam at all times. When possible to do without shielding
gross tumor, attempts should be made to limit the dose to the
optic chiasm to 50 Gy, the retina of at least one eye (but
preferably both) to 50 Gy, and the brain stem to 60 Gy. When
the optic chiasm must be included in the full dose, then there
may be a finite unknown risk of developing blindness.
6.4 Documentation Requirements
A copy of the pretreatment (pre- and post-op)
CT/MRI, the treatment prescription form, treatment calculation
form, simulation films, and representative portal films of each
initial field must be forwarded to RTOG Headquarters within one
week of treatment start. At the completion of treatment, the following
will also be forwarded to Headquarters: daily treatment record,
all isodose distributions including a composite plan, simulation
and portal films of the reduced fields, and the Radiotherapy Form.
6.5 Acute Radiation Toxicities
6.5.1 Expected toxicities
include loss of hair and erythema of the scalp. Reactions in the
ear canals and on the ear should be observed and treated symptomatically.
If significant increase (grades >=3) in reaction of
the normal tissue occurs, it should be noted and reported to the
Study Chairman.
6.5.2 Both acute and delayed
or late reactions to radiotherapy are to be recorded and included
in the complete toxicity evaluation. The level of radiation toxicity
will be scored on a scale of 0-5 as described in Appendix IV-B.
6.5.3 Hematologic toxicities
should be rated on a scale of 0-5 as defined in the RTOG Toxicity
Criteria (Appendix IV-B).
6.5.4 Grade >=3 will
be reported per Appendix V.
6.6 Adverse Reaction Reporting
(RTOG FAX: (215) 928-0153)
6.6.1 All fatal
toxicities (grade 5) resulting from protocol treatment
must be reported by telephone to the Group Chairman, to
RTOG Headquarters Data Management and to the primary Study Chairman
within 24 hours of discovery.
6.6.2 All lifethreatening
(grade 4) toxicities resulting from protocol treatment
must be reported by telephone to the Group Chairman, to
RTOG Headquarters Data Management and to the primary Study Chairman
within 24 hours of discovery.
6.6.3 Appropriate data
forms, and if requested a written report, must be submitted to
Headquarters within 10 working days of the telephone report.
7.1 Topotecan: (NSC #609699, IND#34,494)
7.1.1 Schedule
For the first two cycles of topotecan, each dose
of topotecan will be administered as a 30 minute intravenous infusion
immediately prior to RT. RT must be initiated up to 1/2 to 2 hours
post topotecan infusion. Topotecan will be administered as 0.5
mg/m2/day
five times each week every three weeks for a total of 3 cycles
(Level 1). For the first cycle of topotecan, topotecan
should be administered concurrently with the first 5 treatments,
ideally 5 days a week. For the second cycle, topotecan will be
administered with treatments 16-20. For the first two cycles
of topotecan, topotecan must not be given on days when no radiation
is given. For Level 2,the dose of topotecan will be increased
to 1.0 mg/m2/day.
If toxicity is acceptable
at Level 1. A further dose escalation to 1.5 mg/m2/day
will take place if toxicity is acceptable at Level 2. A maximum
of 3 cycles of topotecan will be administered to each patient.
The time infusion starts and ends and time of radiation treatment
must be recorded on flow sheets.
7.1.2 Names, Chemical
Nature, Classification and Mode of Action (6/3/96)
Topotecan, AS hycamptamine, SK&F 104864-A.
9-dimethyl-10-hydroxycamptothecin. (S)-10-[dimethylaminomethyl]4-ethyl-4,9,-dihydroxy-1-H-pyrano[3',4':6,7]indolizino[1,2-b]
quinoline-3,14(4H,12H)-dione monohydrochloride; molecular formula:
C23H23O5N3.
HCI;MW: 458 daltons. Topoisomerase inhibitor. Binds to the
nuclear enzyme, topoisomerase-1, causing disruption of DNA continuity
and replication.
7.1.3 Physical Description
(6/3/96)
It is supplied as a light-yellow lyophilized powder
in vials containing 4 mg of topotecan AS(as the base) and
48 mg mannitol and 20 mg tartaric acid, NF. The pH is adjusted
to 3.0. It has a reverse magenta label for identification purposes.
Unreconstituted topotecan should be stored at room
temperature 15-30-C (59-86-F) in the light-proof packaging
provided and must be protected from light until it is administered
to patients. Information on expiration dates will be supplied
on a lot-by-lot basis. All cancer chemotherapeutic agents should
be handled with the utmost care during preparation and administration.
To avoid any form of physical contact, the health care provider
should wear gowns, gloves and masks when appropriate. As a parenteral
agent, topotecan should be prepared in a vertical flow biologic
safety cabinet. As an investigational agent, topotecan must be
kept in a secure area and may be supplied only to patients treated
in accordance with this protocol under the direction of the investigator.
The unreconstituted vials contain no antibacterial preservative.
Use within eight hours, unless the vials have been reconstituted
with Bacteriostatic Water USP, in which case vials are good for
21 days at refrigerator temperatures.
7.1.4 Drug Ordering
(6/3/96)
Topotecan AS is supplied through the Pharmacetutical
Management Branch (PMB) for DCTDC-sponsored clinical trials
as 4 mg vials, NSC #609699. Once eligibility is established and
the individual has been registered, drug may be ordered by completing
a NCI Clinical Drug Request (NIH-986) form and mailing
it to PMB, CTEP, DCTDC, NCI, 9000 Rockville Pike, EPN Room 707,
Bethesda, MD 20892, through the DMAS Electronic Clinical Drug
Request System (ECDR) or by Fax (301) 480-4612.
For questions call (301) 496-5725.
7.1.5 Drug Preparation
for Clinical Administration (6/3/96)
Topotecan is to be administered intravenously after
dilution in 0.9% sodium chloride injection or 5% dextrose injection.
UNTIL SPECIFIC COMPATIBILITY DATA ARE AVAILABLE, MIXING TOPOTECAN
WITH OTHER IV FLUIDS OR DRUGS IS NOT RECOMMENDED. TOPOTECAN MUST
NOT BE DILUTED WITH BUFFERED SOLUTIONS BECAUSE OF SOLUBILITY AND
STABILITY CONSIDERATIONS. The lyophilized formulation must be
reconstituted with 4 ml of sterile water for injection, USP, yielding
a 1 mg/ml solution of topotecan AS prior to dilution with .9%
Na Cl or 5% dextrose. Because the lyophilized form contains no
antibacterial preservatives, it is advised that the reconstituted
(undiluted) solution be discarded 8 hours after initial
entry. The final concentration of topotecan solution should be
10-500 µg/ml in 0.9% Na Cl or 6.7-339 µg/ml in 5% dextrose.
The desired amount of drug should be added to an IV solution bag,
mixed and delivered within 24 hours. Remove the needle from the
syringe and replace it with a filter needle. Keep bottle or bag
protected from light. The bottle or bag may be prepared the night
prior to dosing day and stored at refrigerator temperature (2°-8-C).
7.1.6 Discontinuation
of Topotecan
7.1.6.1 For grade 4 hematological
toxicity lasting > 3 days or >= grade 3 nonhematological
toxicity, topotecan will be withheld until resolution of the toxicity
to <= grade 1. Topotecan administration may then be restarted
if medically appropriate at a dose reduced by 25%. If topotecan
must again be withheld because of topotecan-related toxicity,
drug administration will be discontinued. If symptoms are not
manageable the patient goes off protocol therapy. All patients
in whom topotecan or radiation treatment are discontinued will
continue to be monitored for survival. Patients may be treated
as outpatients, but they will remain under direct observation
for at least one hour following the first topotecan administration.
Fever (unrelated to infection) may be treated with antipyretics.
Patients must be supplied with a medical contact who is available
24 hours daily.
7.1.6.2 Tumor progression
documented by CT/MRI scan.
7.1.6.3 Intercurrent illness
which would in the judgement of the investigator require discontinuation
of the drug.
7.1.6.4 Patient request
to withdraw from study.
7.1.7 Drug Inventory
Records
The pharmacist, as a responsible party designated
by the investigator, must maintain a careful record of the inventory
and disposition of all drugs received from DCT, using the NCI
Drug Accountability Record Form (see Investigators Handbook
for Procedures for Drug Accountability and Storage).
7.2 Topotecan Toxicity
Common adverse events reported include mild to moderate
nausea and vomiting, which have been successfully controlled with
anti-emetics (eg. prochlorperazine, or ondansetron). Alopecia,
stomatitis, fever, anorexia, fatigue, elevations of liver function
tests, flu-like symptoms, abdominal pain, dehydration, and diarrhea
have been reported. Cutaneous toxicity has been mostly mild.
Often this has consisted of localized erythema, with or without
pruritus. The major dose-limiting toxicity is topotecan-related
myelosuppression.
7.3 Dose Modification
7.3.1 Toxicity will be
graded according to the criteria in Appendix IV. If any grade
4 (platelets < 25,000 mm3,
granulocytes < 500 mm3)
hematological toxicity lasting > 3
days or any grade 3 or 4 topotecan-related nonhematological toxicity
is observed in any patient and is not controlled acutely by palliative
measures, topotecan administration to that patient will cease
immediately. Topotecan will be withheld until resolution of the
toxicity to <= grade 1. Topotecan administration may then
be restarted if medically appropriate at a dose reduced by 25%.
If topotecan must again be withheld because of topotecan-related
toxicity, drug administration will be discontinued. Cranial radiation
will continue unless toxicity is attributed to radiation, in which
case radiation will be held until toxicity resolves.
7.3.2 This study will involve a dose escalation of topotecan
in three increments 0.5, 1.0 and 1.5 mg/m2/day
x 5 days q 3 weeks x maximum 3 cycles. Ten evaluable patients
will be analyzed at each dose level. To be evaluable a patient
must have received treatment and be analyzed at week 15 for toxicity.
After 10 evaluable cases have treatment results available, these
cases will be analyzed with respect to unacceptable toxicity (defined
at >= grade 3 nonhematological or >= grade 4 hematological
toxicity lasting >7 days). If any fatal toxicities occur,
accrual will be immediately suspended for that dose level and
the study will be re-evaluated. (1/31/96)
7.3.3 The study chair
and RTOG protocol office must be notified of each event of unacceptable
toxicity (patient number, toxicity, toxicity grade, relationship
to protocol treatment, duration, outcome - if known) within
3 working days of onset, to minimize the risk that the study will
continue to inappropriately accrue patients to a dose level.
7.4 Adverse Reaction Reporting (RTOG
FAX: (215) 928-0153)
7.4.1 Any Adverse
Event
All adverse events, regardless of severity and whether
or not ascribed to topotecan, are to be recorded on the appropriate
data form. Patients withdrawn from the study due to any adverse
event will be followed.
7.4.2 Serious Adverse
Event
According to Federal Regulation 21 CFR 312.32, a
serious adverse event is defined as any experience that suggests
a significant hazard, contraindication, side effect, or precaution.
With respect to human clinical experience, a serious adverse drug
event includes any experience that is fatal or life-threatening,
permanently disabling, requires inpatient hospitalization, or
is a congenital anomaly, cancer, or overdose.
7.4.2.1 Serious adverse
events must be reported to:
a. The IRB - To comply with Federal
Regulations, each investigator will make an accurate and special
report to the IRB on all serious adverse events, deaths, or life-threatening
problems which were not previously anticipated (in nature,
severity, or degree of incidence) and which may reasonably
be regarded as caused by or associated with topotecan.
b. IDB/NCI and RTOG - To provide IDB/NCI
and RTOG with enough information to adequately assess the overall
safety profile of the investigational drug, each investigator
shall make an accurate and special report to IDB/NCI on all
serious adverse events, deaths, or life-threatening problems whether
unanticipated or not.
Fax (301) 230-0159
c. Report Time Requirements - Report
to Investigational Drug Branch by telephone (301-230-2330)
or fax (301-230-0159) within 24 hours:
In the event of any grade >= 3 non-hematologic
toxicity or grade >= 4 hematologic toxicity, RTOG Headquarters
is to be notified by phone within 24 hours and appropriate data
forms submitted within 7 days.
Not applicable to this study.
9.1 Corticosteroids and Other Medication
9.1.1 Corticosteroids
may be utilized as deemed necessary by the individual investigator.
Corticosteroids will be used in the smallest dose that will afford
the patient satisfactory neurologic function and the best possible
quality of life.
9.1.2 Phenytoin sodium
and other anti-seizure medication may be used as indicated clinically.
All medications and doses are to be documented.
9.1.3 Infections are to
be treated with appropriate antibiotics and recorded. If infection
precludes topotecan therapy for more than two weeks, the patient
will be discontinued from the study.
9.1.4 Analgesics, antiemetics,
and any other medications are to be specified, and their doses
recorded.
9.2 Additional treatment for disease progression
9.2.1 Disease recurrence
or progression should be documented by neurologic examination
and CT/MRI. Appropriate therapy will then be administered at the
discretion of the investigator. Such therapy may consist of additional
chemotherapy, repeat surgery, placement of a shunt, interstitial
brachytherapy, radiosurgery, or supportive care. All therapy shall
be documented.
9.2.2 Every effort will
be made to ensure patient comfort at all times. Patients will
be informed that their elective withdrawal from this protocol
will in no way jeopardize their care, and they will be encouraged
to continue their follow-up therapy independent of participation
in this study.
Not applicable to this study.
11.1 Study Parameters Table
*Note: It is mandatory that patients are followed with the
same study (CT or MRI) as the baseline study.
11.2 Evaluation During Study
11.2.1 A neurologic examination will be performed once
a week during radiation therapy, at initiation of each chemotherapy
cycle and at each follow-up visit.
11.2.2 Skin within the treatment portal will be examined
at least once per week during radiation therapy and first post-treatment
visit. The degree of skin reaction should be recorded. If moist
desquamation develops, or is threatening to develop in an area
that is larger than 1-2 cm in diameter, then the study chairman
should be notified immediately and therapy (topotecan and RT)
should be interrupted for a few days to allow for healing.
11.2.3 The contrast-enhanced CT/MRI of the brain will be
obtained prior to surgery and prior to radiotherapy (post-surgery),
and at intervals specified in Section 11.1 and at the time of
neurologic deterioration unless the last CT/MRI done was within
one month and was compatible with recurrence. Attention is drawn
to the occurrence of "early delayed radiation reactions"
that occur usually with the first two weeks post-treatment and
last up to 6-8 weeks. These transient adverse signs and symptoms
spontaneously improve without therapy. They are considered to
be due to transient demyelination.36
Caution is, therefore, urged in diagnosing and treating recurrent
tumor during the first two or three months post-irradiation.
CT/MRI is not required after documentation of tumor progression
or recurrence.
11.3 Criteria for Evaluation of Toxicity
11.3.1 As per Section
13.2 this study is to evaluate toxicity and determine optimum
dose of topotecan combined with cranial radiation for malignant
gliomas.
11.3.2 Post-mortem examination
for the cranial contents should be obtained at death whenever
possible to evaluate effects of this therapy on malignant and
normal brain tissue. It is especially important that if deaths
occur on study or within 30 days of topotecan administration,
an autopsy must be sought by the treating physician.
11.4 Follow-up for Cancelled and Ineligible
Cases
11.4.1 Eligible patients
who refuse all treatment will be cancelled and removed from follow-up.
11.4.2 All cases receiving
any topotecan will be followed for survival and morbidity data.
11.4.3 Ineligible cases
who do not receive any protocol therapy will not be followed.
12.1 Summary of Data Submission
12.2 Recording of Toxicity
All toxicities >=
grade 3 must be documented on the Study-Specific Flowsheets as
to date of onset and date of resolution to <= grade
2.
13.0 STATISTICAL CONSIDERATIONS
13.1 Study Endpoints
13.1.1 Toxicity
13.2 Sample Size
(1/31/96)
This study will involve a dose escalation of topotecan
in three increments 0.5, 1.0 and 1.5 mg/m2/day
x 5 days q3 weeks x maximum 3 cycles. To be evaluable, a patient
must have received treatment and be analyzed at week 15 for toxicity.
After 10 evaluable cases have treatment results available, these
cases will be analyzed with respect to unacceptable toxicity (defined
at >= grade 3 nonhematological or >= grade 4 hematological
toxicity lasting >7 days). If any fatal toxicities occur,
accrual will be immediately suspended for that dose level and
the study will be re-evaluated. If there are no fatal toxicities
and 0 patients with unacceptable toxicity, the dose of topotecan
be escalated. If 1 of the first 5 patients or 2 of 10 patients
have unacceptable toxicity, accrual will continue until 5 additional
cases are evaluated with treatment results. These 5 cases will
be analyzed with respect to toxicity and if 0 or 1 of these patients
have unacceptable toxicity then the dose can be escalated. If
there are >=3 patients of the first 10 patients in a cohort
or >= 4 of the 15 patients in a cohort with unacceptable toxicity,
the previous topotecan dose level will be accepted as the maximally
tolerated dose. Total sample size will be maximum of 45 patients.
All treated patients will be considered for toxicity evaluation.
13.3 Patient Accrual
The patient accrual is projected to be 9 cases per
month, based upon the monthly accrual for RTOG 94-11. At that
rate, it will take six months for the required accrual for the
phase I study. If the average monthly accrual rate is less than
three patients, the study will be re-evaluated with respect to
feasibility.
13.4 Suspension of Accrual Due to Morbidity
If there is any fatal treatment morbidity, the
accrual will be suspended, and all data pertaining to the event
will be reviewed by the study chairs and reported to the RTOG
Data Monitoring Committee (DMC) for review.
13.5 Dose Escalation
(1/31/96)
Dose escalation of topotecan will be in three increments
of 0.5, 1.0 and 1.5 mg/m2/day x 5 days q 3 weeks x maximum 3 cycles.
Each dose level will be evaluated when 10 evaluable patients
have survived 15 weeks from the start of therapy. If no unacceptable
toxicities are observed, then the dose of topotecan will be escalated.
If 1 or 2 unacceptable toxicities are observed within the first
10 evaluable patients, then five additional evaluable patients
will be accrued. If fewer then three acceptable toxicities occur
within the first 15 evaluable patients then the dose will be escalated.
If three or more unacceptable toxicities are observed then the
previously acceptable dose of topotecan will be accepted as the
maximum tolerated dose.
13.6 Analyses Plans
13.6.1 Interim analyses
Interim reports with statistical analyses are prepared
every six months until the initial manuscript reporting the treatment
results has been submitted. In general, the interim reports will
contain information about:
a) the patient accrual rate with a projected completion
date for the accrual phase;
b) the quality of submitted data with respect to
timeliness, completeness, and accuracy;
c) the frequency and severity of the toxicities.
Through examining the above items, the RTOG DMC
and the statistician can identify problems with the execution
of the study. These problems will be reported to the RTOG committee
responsible for this study and, if necessary, the RTOG Executive
Committee, so that corrective action can be taken.
13.6.2 Analysis
for Reporting the Initial Treatment Results (1/31/96)
This analysis will be undertaken when each patient
has been potentially followed for 15 weeks. The usual components
of this analysis are:
a) tabulation of all cases entered, and any excluded
from the analysis with reasons for the exclusion:
b) reporting institutional accrual;
c) distribution of important prognostic baseline
variables by treatment arm;
d) observed results with respect to the endpoints
described in Section 13.1. Further subgroup analyses will not
be undertaken due to the small sample size.
° occasional anorexia
° hair loss
° fatigue
° occasional diarrhea, skin rash, fever
° dysuria (one patient)
° occasional elevations in bilirubin or transaminases
- Institution name and number
- Patient's name and ID number
- Verifying physician's name
- Eligibility criteria information
- Demographic data
- Treatment start date
(x 109/L)
Investigational Drug Branch
P.O. Box 30012
Bethesda, MD 20824
Phone (301) 230-2330
(available 24 hours)
Fax (301) 230-0159RTOG ADR
Calls to RTOG should be made to the Study Research Associate
Phone (215) 574-3150
Fax (215) 928-0153
Copies of each report will be kept in the investigator's
files and adequate documentation provided to IDB/NCI that the
IRB has been properly notified.
Item Due Demographic Form (A5)
Baseline Mini Mental Status Evaluation (MS)Within 1 wk of study
entry Initial Evaluation Form (I1)
Diagnostic Pathology Report (P1) Study-Specific Flowsheet (SF)(pre-study labs)Within 2 wks of study entry Preliminary dosimetry information:
RT prescription (Protocol Treatment Form) (T2)
Films (simulation and portal) (T3)
Calculations (T4)
Pretreatment (pre- and post-op)
CT/MRI scans (C1) and reports (C3)Within
1 wk of start of RT Radiotherapy form (T1)
Final dosimetry information:
Daily treatment record (T5)
Isodose distribution (T6)
Boost films (simulation and portal) (T8)
Study-specific flowsheet (SF)Within 1 wk of RT
end Post RT/CT/MR scan (C2) and reports (C3)
3 months from start of RT Study-Specific Flowsheet (SF) One month from last dose of topotecan Follow-up form (F1)
Mini mental status evaluation (MS)Every 3 months from
treatment start for 1 yr; q4
months x 1 yr, q6 months x 3 yrs, then annually.
Also
at progression/relapse and at death (F1 only). Adverse event form (K4) As applicable
Autopsy report (D3) As applicable
1. Walker MD, Green SB, Byar DP et al. Randomized
comparisons of radiotherapy and nitrosoureas for the treatment
of malignant glioma after surgery. N Engl J Med 1980; 303: 1323-1329.
2. EORTC Brain Tumour Group. Effect of CCNU on survival
rate of objective remission and duration of free interval in patients
with malignant brain glioma - final evaluation. Eur J Cancer 1978;
14: 851-856.
3. Kornblith PL, Walker M. Chemotherapy for malignant
gliomas. J Neurosurg 1988; 68: 1-17.
4. Fine HA, Dear KB, Loeffler JS, et al. Meta-analysis
of radiation therapy with and without adjuvant chemotherapy for
malignant gliomas in adults. Cancer 1993; 71: 2585-2597.
5. Schold SC Jr, Herndon JE, Burger PC, et al. Randomized
comparison of diaziquone and carmustine in the treatment of adults
with anaplastic gliomas. J Clin Oncol 1993; 11: 77-83.
6. Bigner DD. Biology of gliomas: potential clinical
implications of glioma cellular heterogeneity. Neurosurgery 1981;
9: 320-326.
7. Kornblith PL, Szypko PE. Variations in response
of human brain tumours to BCNU in vitro. J Neurosurg 1978;
48: 580-586.
8. Yung WA, Shapiro JR, Shapiro WR. Heterogeneous
chemosensitivities of subpopulations of human glioma cells in
culture. Cancer Res 1982; 42: 992-998.
9. Vick NA, Khandekar JD, Bigner DD. Chemotherapy
of brain tumours: the "blood-brain barrier" is not a
factor. Arch Neurol 1977; 34: 523-526.
10. Lesser GJ, Grossman S. The chemotherapy of high-grade
astrocytomas. Sem Oncology 1994; 21: 220-235.
11. Neuwelt EA, Howieson J, Fenkel EP, et al. Therapeutic
efficacy of multiagent chemotherapy with drug delivery enhancement
by blood-brain barrier modification in glioblastoma. Neurosurgery
1986; 19: 573-582.
12. Gumerlock MK, Belshe BD, Madsen R, et al. Osmotic
blood-brain barrier disruption and chemotherapy in the treatment
of high grade malignant glioma: Patient series and literature
review. J Neurooncol 1992; 12: 33-46.
13. Mahaley MS Jr, Hipp SW, Dropcho EJ, et al. Intracarotid
cisplatin chemotherapy for recurrent gliomas. J Neurosurg 1989;
70: 371-378.
14. Shapiro WR, Green SB, Burger PC, et al. A randomized
comparison of intra-arterial versus intravenous BCNU, with or
without intravenous 5-fluorouracil, for newly diagnosed patients
with malignant glioma. J Neurosurg 1992; 76: 772-781.
15. Brem H, Mahaley MS Jr, Vick NA, et al. Interstitial
chemotherapy with drug polymer implants for the treatment of recurrent
gliomas. J Neurosurg 1991; 74: 441-446.
16. Fine HA, Antman KH. High-dose chemotherapy with
autologous bone marrow transplantation in the treatment of high
grade astrocytomas in adults: Therapeutic rationale and clinical
experience. Bone Marrow Transplant 1992; 10: 315-321.
17. NCI Annual Report to the Food an Drug Administration:
Topotecan HCI (NSC 609 699), IND 34494, June 1991.
18. SmithKline Beecham Pharmaceuticals. Investigator
Brochure. Topotecan SK&F 104864-A, 1994.
19. Lock RB and Ross WE. DNA Topoisomerases in cancer
Therapy. Anticancer Drug Design, 1987; 2: 151-164.
20. Eng WK, Faucette L, Johnson RK, et al. Evidence
that DNA topoisomerase I is necessary for the cytotoxic effects
of camptothecin. Molecular Pharm, 1989; 34: 755-760.
21. Johnson RK, McCabe FL, Faucette LF, et al. SK&F
104864, A Water-Soluble Analog of Camptothecin with a Broad Spectrum
of Activity in Preclinical Tumour Models. Proc Am Assoc Cancer
Res 1989; 30: 623.
22. Burris H, Kuhn J, Johnson R, et al. SKF 104864:
Preclinical studies of a new topoisomerase I inhibitor. Proc Am
Assoc Cancer Res 1990; 31: 431.
23. Sirott MN, Saltz L, Young C, et al. Phase I and
clinical pharmacologic study of intravenous topotecan. Proc Am
Soc Cin Oncol 1991; 10: 104.
24. Rowinsky E, Grochow L, Hendricks C, et al. Phase
I and pharmacologic study of topotecan (SK&F 104864): A novel
topoisomerase I inhibitor. J Clin Oncol 1992; 10: 647-656.
25. Verweij J, Lund B, Beynen J, et al. Clinical
studies with topotecan: The EORTC experience. Proc 7th NCI-EORTC
symposium on New drugs in cancer therapy. Ann Oncol 1992; Suppl
1, 3: 118.
26. Boothman DA, Wang M, Schea RA, et al. Posttreatment
exposure to camptothecin enhances the lethal effects of x-rays
on radioresistant human malignant melanoma cells. Int J Radiat
Oncol Biol Phys 1992; 24: 939-948.
27. Mattern MR, Hofmann GA, McCabe FL, Johnson RK.
Synergistic cell killing by ionizing radiation and topoisomorase
I inhibitor Topotecan (SK & F 104864). Cancer Res 1991; 51:
5813-5816.
28. Kim JH, Kim SH, Kolozsvary A, Khil MS. Potentiation
of radiation response in human carcinoma cells in vitro
and murine fibrosarcoma in vivo by topotecan, an inhibitor
of DNA topoisomerase I. Int J Radiat Oncol Biol Phys 1992; 22:
515-518.
29. Boscia RE, Korbut T, Holden SA, et al. Interaction
of topoisomerase I inhibitors with radiation in cis-diamminedichloroplatinum
(II)-sensitive and -resistant cells in vitro and in the
FSaIIC fibrosarcoma in vivo. Int J Cancer 1993; 53: 118-123.
30. Friedman HS, Houghton PJ, Schold SC, et al. Activity
of 9-dimethylaminomethyl-10-hydroxycamptothecin against pediatric
and adult central nervous system tumor xenografts. Cancer Chemother
Pharmacol 1994; 34: 171-174.
31. Blaney SM, Cole DE, Balis FM, et al. Plasma and
cerebrospinal fluid pharmacokinetic study of Topotecan in nonhuman
primates. Cancer Res 1993; 53: 725-727.
32. Pratt CB, Stewart C, Santana VM, et al. Phase
I study of topotecan for pediatric patients with malignant solid
tumors. J Clin Oncol 1994; 12: 539-543.
33. Eisenhauer EA, Wainman N, Boos G, et al. Phase II trials of topotecan in patients (pts) with malignant glioma and soft tissue sarcoma (abstract 488). Proc Am Soc Clin Oncol 1994; 13: 175.
RESEARCH STUDY
I have the right to know about the procedures that
are used in my participation in clinical research so I have an
opportunity to decide whether or not to undergo the procedure
after knowing the risks and hazards involved. This disclosure
is an effort to make me better informed so I may give or withhold
my consent to participate in clinical research.
PURPOSE OF THE STUDY
I understand that I have been diagnosed with a malignant
brain tumor called a glioblastoma multiforme and further treatment
is recommended. The usual treatment in cases such as mine is radiation
therapy given once daily, five days per week for six weeks. Radiation
therapy is a form of cancer treatment using high energy x-rays
and can be given with or without either chemotherapy or other
medications.
This study is being done to assess the side effects
when topotecan, a new medicine, is given together with radiation
therapy. Forty-five patients will be treated on this study.
DESCRIPTION OF PROCEDURES
This study involves daily radiation treatments to
the part of my brain involved with tumor. Radiation treatments
will be given five times a week for six weeks. Topotecan will
be given before my radiation five times a week as an intravenous
("i.v.", in my vein) over 30 minutes. I will
receive topotecan during the first and fourth weeks of radiation
treatment. A third course of topotecan will be given during the
week following radiation. The Division of Cancer Treatment, National
Cancer Institute will provide topotecan free of charge for this
study but should this agent become commercially available or approved
for this indication during the course of this study, however,
I may be asked to purchase subsequent doses of the medication.
RISKS AND DISCOMFORTS
Cancer treatments often have side effects. The treatment
used in this program may cause all, some, or none of the side
effects listed. In addition, there is always the risk of very
uncommon or previously unknown side effects occurring.
Risks from Radiation Therapy:
include some or all of the following side effects: scalp redness,
or soreness, hair loss, which may be temporary or permanent, dry
mouth or altered taste, hearing impairment, fatigue, sleepiness
or temporary aggravation of tumor symptoms such as headaches,
seizure, or weakness. Cataracts may occur, although every effort
will be made to minimize the chances of this occurring. Radiation
sometimes causes late side effects such as mental slowing or behavioral
change. Occasionally radiation causes severe local damage to normal
brain tissue, a condition called necrosis. Radiation necrosis
can mimic recurrent brain tumor or those of a stroke and may require
surgery.
Risks from Topotecan:
include appetite loss, sore mouth, fever, flu-like illness, abdominal
pain, dehydration, severe diarrhea, and mild to moderate nausea
and vomiting which have been successfully controlled with antiemetics.
Hair loss and skin rashes usually with itching have been reported.
A temporary drop, sometimes very severe, in the level of red
blood cells, white blood cells and/or platelets in the blood occurs
and this may put me at risk of infection or bleeding. Temporary
changes in blood tests of liver or kidney function have been seen.
Topotecan might increase the risk of early or delayed damage to
the brain that can be seen with radiation therapy alone. With
any treatment there is a small risk of new or unexpected side
effects, including death occurring. Contraceptive precautions
must be taken.
My physician will be checking me closely to see if
any of these side effects are occurring. Routine blood tests
will be done to monitor the effects of treatment. Side effects
usually disappear after the treatment is stopped. In the meantime,
my doctor may prescribe medication to keep these side effects
under control. I understand that the use of medication to help
control side effects could result in added costs. This institution
is not financially responsible for treatments of side effects
caused by the study treatment.
This study may be harmful to an unborn child. There
is insufficient medical information to see whether there are significant
risks to a fetus carried by a mother who is participating in this
study. Therefore, participants who are still menstruating and
have not been surgically sterilized must have a negative pregnancy
test prior to participating in this study. This requires that
a small amount of blood be drawn within 7 days prior to the study.
The results will be made available to me prior to the initiation
of this study. There may be laboratory testing and procedures
required by this study for research purposes. These additional
tests may increase my medical bills although the impact will be
dependent on my insurance company.
CONTACT PERSONS
In the event that injury occurs as a result of this
research, treatment will be available. I understand, however,
I will not be provided with reimbursement for medical care other
than what my insurance carrier may provide nor will I receive
other compensation. For more information concerning the research
and researchrelated risks or injuries, I can notify Dr.
______________________, the investigator in charge at __________________________. In addition, I may
contact _____________________________ at _____________________________ for information regarding patients' rights in research
studies.
BENEFITS
It is not possible to predict whether or not any
personal benefit will result from the treatment program. I understand
that the information which is obtained from this study may be
used scientifically and possibly be helpful to others. The possible
benefits of this treatment program are greater shrinkage and control
of my tumor and prolongation of my life but I understand this
is not guaranteed.
I have been told that should my disease become worse,
should side effects become very severe, should new scientific
developments occur that indicate the treatment is not in my best
interest, or should my physician feel that this treatment is no
longer in my best interest, the treatment would be stopped. Further
treatment would be discussed.
ALTERNATIVES
Alternatives which could be considered in my case
include either surgery or radiation therapy either alone or with
chemotherapy or treatments to make me feel better, but not necessarily
cure me or make my disease less. An additional alternative is
no further therapy, which would probably result in continued growth
of my tumor. I understand that my doctor can provide detailed
information about my disease and the benefits of the various treatments
available. I have been told that I should feel free to discuss
my disease and my prognosis with the doctor. The physician involved
in my care will be available to answer any questions I have concerning
this program. In addition, I understand that I am free to ask
my physician any questions concerning this program that I wish
in the future.
My physician will explain any procedures related
solely to research. Some of these procedures may result in added
costs but may be covered by insurance. My doctor will discuss
these with me.
VOLUNTARY PARTICIPATION
Participation in this study is voluntary. No compensation
for participation will be given. I understand that I am free
to withdraw my consent to participate in this treatment program
at any time without prejudice to my subsequent care. Refusal
to participate will involve no penalty, or loss of benefits.
I am free to seek care from a physician of my choice at any time.
If I do not take part in or withdraw from the study, I will continue
to receive care. In the event of a researchrelated injury,
I understand my participation has been voluntary.
CONFIDENTIALITY
I understand that records of my progress while on
the study will be kept in a confidential form at this institution
and also in a computer file at the headquarters of the Radiation
Therapy Oncology Group (RTOG) . The confidentiality of
the central computer record is carefully guarded. During their
required reviews, representatives of the Food and Drug Administration
(FDA), the National Cancer Institute (NCI), qualified
representatives of applicable drug manufacturers, and other groups
or organizations that have a role in the conduct of this study
may have access to medical records which contain my identity.
However, no information by which I can be identified will be
released or published. Histopathologic material, including tissue
and/or slides, may be sent to a central office for review and
research investigation associated with this protocol.
I have read all of the above, asked questions,
received answers concerning areas I did not understand, and willingly
give my consent to participate in this program. Upon signing
this form I will receive a copy.
___________________________ Patient Signature (or Legal Representative)
______________ Date
| 100 | Normal; no complaints; no evidence of disease |
| 90 | Able to carry on normal activity; minor signs or symptoms of disease |
| 80 | Normal activity with effort; some sign or symptoms of disease |
| 70 | Cares for self; unable to carry on normal activity or do active work |
| 60 | Requires occasional assistance, but is able to care for most personal needs |
| 50 | Requires considerable assistance and frequentmedical care |
| 40 | Disabled; requires special care and assistance |
| 30 | Severely disabled; hospitalization is indicated, although death not imminent |
| 20 | Very sick; hospitalization necessary; active support treatment is necessary |
| 10 | Moribund; fatal processes progressing rapidly |
| 0 | Dead |
N F
Definition No neurologic symptoms; fully active at home/work without assistance. Minor neurologic symptoms; fully active at home/work without assistance. Moderate neurologic symptoms; fully active at home/work but requires assistance. Moderate neurologic symptoms; less
than fully active at home/work and requires assistance.
Severe neurologic symptoms; totally
inactive requiring complete assistance at home or in institution-unable
to work.
A neurological evaluation and assignment to a functional
class will be performed for each patient in the study. The patient
will be classified as below:
Class I Able to work, neurological findings minor or absent.
Class II Able to be at home although nursing care may be required. Neurological findings present
but not serious.
Class III Requiring hospitalization and medical care with major neurological findings.
Class IV Requiring hospitalization and
in serious physical or neurological state including coma.
Class Ability to Work Hospital (bed) Neurologically Impaired
I + 0,1
II to + 2
III + to + 3
IV 4
Neurological Symptoms
(to be scored as follows: 0absent, 1mild,
2moderate, 3severe)
Neurological Signs
(to be scored as follows: 0normal, 1mildly
impaired, 2moderately impaired, 3severely impaired)
A. GENERAL GUIDELINES
In order to assure prompt and complete reporting of toxicities, the following general guidelines are to be observed. These apply to all RTOG studies and Intergroup Studies in which RTOG participates. When a protocol toxicity requires special handling, study-specific reporting procedures supercede the General Guidelines.
1. The Principal Investigator
will report the details of any unusual, significant, fatal or
lifethreatening protocol treatment reaction to the RTOG
Group Chairman. In the absence of the Group Chairman, the report
should be made to the Headquarters Data Management Staff (215/5743214).
When telephone reporting is required, the Principal Investigator
should have all relevant material available. See the protocol-specific
criteria to grade the severity of the reaction.
2. The Principal Investigator
will also report the details of the significant reaction to the
Study Chairman by telephone .
3. A written report containing
all relevant clinical information concerning the reported event
will be sent to RTOG Headquarters by the Principal Investigator.
This must sent within 10 working days of the discovery of the
toxicity unless specified sooner by the protocol (FAX #215/9280153).
4. The Group Chairman
in consultation with the Study Chairman will take appropriate
and prompt action to inform the membership and statistical personnel
of any protocol modifications and/or precautionary measures.
5. For those incidents
requiring telephone reporting to the National Cancer Institute
(NCI), Investigational Drug Branch (IDB) or Food
and Drug Administration (FDA), the Principal Investigator
should first call RTOG (as outlined above) unless this
will unduly delay the notification process required by the federal
agencies.
A copy of all correspondence submitted to NCI,
or to another Cooperative Group (in the case of RTOG-coordinated
intergroup studies) must also be submitted to RTOG Headquarters
when applicable.
6. The Principal Investigator,
when participating in RTOG-coordinated Intergroup studies, is
obligated to comply with all additional reporting specifications
required by an individual study.
7. Institutions must
also comply with their individual Institutional Review Board policy
with regard to toxicity reporting procedure.
8. Failure to comply
with reporting requirements in a timely manner may result in suspension
of patient registration.
B. RADIATION TOXICITY GUIDELINES
1. All fatal toxicities (grade 5)
resulting from protocol treatment must be reported by telephone
to the Group Chairman, to RTOG Headquarters Data Management and
to the primary Study Chairman within 24 hours of discovery.
2. All lifethreatening (grade 4)
toxicities resulting from protocol treatment must be reported
by telephone to the Group Chairman, to RTOG Headquarters
Data Management and to the primary Study Chairman within 24 hours
of discovery.
3. Appropriate data forms, and if requested a written
report, must be submitted to Headquarters within 10 working days
of the telephone report.
C. ADVERSE DRUG REACTIONS DRUG AND BIOLOGICS
An adverse reaction is a toxicity or an undesirable
effect usually of severe nature. Specifically, this may include
major organ toxicities of the liver, kidneys, cardiovascular system,
central nervous system, skin, bone marrow, or anaphylaxis. These
undesirable effects may be further classified as "known"
or "unknown" toxicities.
Known toxicities
are those which have been previously identified as having resulted
from administration of the agent. They may be identified in the
literature, the protocol, the consent form or noted in the drug
insert.
Unknown
toxicities are those thought to have resulted from the agent but
have not previously been identified as a known side effect.
Commercial and NonInvestigational Agents
i. Any fatal (grade 5) or life threatening (grade 4) adverse reaction which is due to or suspected to be the result of a protocol drug must be reported to the Group Chairman or to RTOG Headquarters' Data Management Staff and to the Study Chairman by telephone within 24 hours of discovery. Known grade 4 hematologic toxicities need not be reported by telephone.
ii. Unknown adverse reactions (> grade
2) resulting from commercial drugs prescribed in an RTOG protocol
are to be reported to the Group Chairman or RTOG Headquarters'
Data Management, to the Study Chairman and to the IDB within 10
working days of discovery. FDA Form 3500 is to be used in reporting
details. All relevant data forms must accompany the RTOG copy
of Form 3500.
iii. All neurotoxicities (> grade 3)
from radiosensitizer or protector drugs are to be reported within
24 hours by phone to RTOG Headquarters and to the Study Chairman.
iv. All relevant data forms must be submitted to
RTOG Headquarters within 10 working days on all reactions requiring
telephone reporting. A special written report may be required.
Reactions definitely thought not to be treatment related should not be reported, however, a report should be made of applicable effects if there is a reasonable suspicion that the effect is due to protocol treatment.
Investigational Agents
Prompt reporting of adverse reactions in patients
treated with investigational agents is mandatory. Adverse reactions
from NCI sponsored drugs are reported to:
>
- All deaths during therapy with the agent. Report
by phone within 24 hours to IDB and RTOG Headquarters.
**A written report to follow within
10 working
days.
- All deaths within 30 days of termination of the agent. As above.
- All life threatening (grade 4) events which may be due to agent. As above.
- First occurrence of any toxicity (regardless of grade). Report by phone within 24 hours to IDB drug monitor and RTOG Headquarters.
**A written report may be
required.
**
See attached NCI Adverse Drug Reaction Reporting Form
- All fatal (grade 5) and life threatening (grade 4) known adverse reactions
due to investigational agent. Report by phone to RTOG Headquarters and the Study Chairman within 24 hours
**A written report must be sent to RTOG
within working days with a copy to
IDB.
(Grade 4 myelosuppression not reported
to
IDB)
- All fatal (grade 5) and life threatening (grade 4) unknown adverse
reactions resulting from or suspected to be
related to investigational agent.
Report by phone to RTOG Headquarters, the Study Chairman and IDB within 24 hours.
**A written report to follow within 10 working days.
- All grade 2, 3 unknown adverse
reactions resulting from or suspected to be
related to investigational agent.
**Report in writing to RTOG Headquarters and IDB within 10 working days.