Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
to Improve Outcomes
and Minimize Toxicities
in Radiation Therapy
San Francisco, Calif., USA, November 4, 2001
Guest Editor
Gillian M. Thomas, Toronto, Canada
Fax + 41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
Vol. 63, Suppl. 2, 2002
Contents
1 Foreword
Thomas, G.M. (Toronto)
Foreword
A variety of techniques are now available to radiation study of patients with head and neck cancers. Other
oncologists to optimize treatment of cancers, including potential applications of amifostine are reviewed in the
altered fractionation schedules, enhanced image guidance, article by Dr. Grdina and colleagues, along with recent
intensity modulation allowing radiation dose escalation advances in the development of newer cytoprotectants to
and improved brachytherapy techniques. In recent years, reduce the acute and chronic toxicities associated with
there has been increasing interest in the concurrent or high-dose treatment strategies and aggressive combined
sequential use of chemotherapeutic agents with radiosensi- modality protocols.
tizing ability to enhance the effectiveness of radiotherapy. The occurrence of anemia in cancer patients is an often
These agents include cisplatin, 5-fluorouracil, taxanes, to- overlooked complicating factor that is associated with
potecan, gemcitabine, vinorelbine, and tirapazamine. In poorer outcome possibly by decreasing the response to
certain malignancies (e.g., non-small-cell lung cancer, head radiotherapy, presumably via lowering the oxygen-carry-
and neck cancers, esophageal cancer and cervical cancer), ing capacity of the blood and thus exacerbating intratu-
concurrent chemotherapy and radiotherapy protocols have moral hypoxia. In addition, anemia has an adverse effect
resulted in better tumor control and/or patient survival on the quality of life of cancer patients, as evidenced by
than with radiotherapy alone. The review by Dr. Curran in the increased fatigue that has been associated with low
this supplement provides an update of recent clinical trials hemoglobin levels. Studies in various types of cancers
in this area, and emphasizes that while much has been have indicated that a high proportion of patients are
achieved in the quest for new combined modality regimens anemic prior to or during radiotherapy, and that low
capable of improving the outcomes for patients with can- hemoglobin levels are associated with poor clinical out-
cer, important questions concerning the selection of pa- comes with radiotherapy. As emphasized in other articles
tients, and the optimal dosages and timing of sequential in this supplement, these findings underline the impor-
therapies remain to be answered in future studies. tance of early detection and treatment of anemia in cancer
Other evolving approaches to optimizing radiotherapy patients. Administration of epoetin alfa to correct anemia
include the use of radioprotectants to reduce radio- has been reported to enhance locoregional response rates
therapy-induced toxicity without affecting its antitumor to chemoradiation therapy in patients with certain types
efficacy, cytotoxic agents such as mitomycin C to specifi- of cancers (e.g., oropharyngeal squamous cell carcinomas)
cally target hypoxic tumor cells, and strategies to counter and to improve quality of life. Whether epoetin alfa thera-
anemia such as treatment with epoetin alfa (recombinant py will also increase long-term survival is currently being
human erythropoietin). It is postulated that anemia in investigated. Other ongoing studies are investigating
cancer patients may result in a poor treatment outcome whether epoetin alfa may also be effective in protecting
because of an increased resistance to radiation or chemo- against radiotherapy-induced neurotoxicity.
therapy. Radioprotectants currently under investigation The challenge for the future is to utilize our present
include amifostine (WR-1065), which has been shown in knowledge to optimize the management of cancer pa-
experimental studies to prevent both radiation-induced tients undergoing radiotherapy or combined modality
cell death and radiation-induced mutagenesis. Moreover, protocols with the objective of improving both the out-
this agent reduced the incidence of early and late radio- come of treatment and quality of life.
therapy-induced xerostomia in a multicenter clinical Gillian M. Thomas
Dexrazoxane
Dexrazoxane (ICRF-187) is a cyclic derivative of the Relationship Between the Net Charge of Thiol
metal-chelating agent ethylenediamine-tetraacetic acid Compounds and Their Ability to Protect
(EDTA) that provides protection against the cardiotoxici- Against Radiation-Induced DNA Damage
ty of anthracycline-based chemotherapeutic agents, such
as doxorubicin. Although the risk of cardiotoxicity ap- The mechanism by which radiation induces DNA
pears to be reduced with newer formulations, such as damage is slightly different to that of chemotherapeutic
peglyated liposomal doxorubicin [8], cardiotoxicity is a agents. Radiation-induced damage is introduced into a
well-recognized, serious, treatment-limiting adverse ef- genome by either a direct action, where the energy is
fect of these compounds. It occurs via the generation of deposited directly on the genome, or indirectly via the for-
reactive oxygen species, which are highly toxic to cardiac mation of free radicals which are responsible for the resul-
tissues, by the stable complexes formed between anthra- tant cell killing, mutagenesis, transformation, and carci-
cycline drugs and iron [9]. The cardioprotective effect of nogenesis. The latter mechanism, which accounts for
dexrazoxane is believed to result from its intracellular about 75% of radiation-induced DNA damage by pho-
metabolism to a ring-opened hydrolysis product (ICRF- tons, can be abrogated with free radical scavengers
198), which is a strong chelator of free and bound intracel- present in the local microenvironment at the time the free
lular iron in the myocardium. As a consequence, the radicals are formed. However, in the case of direct dam-
amount of iron available to form complexes with anthra- age, there are no known radioprotectants as this process
cyclines is reduced and formation of the reactive oxygen occurs too rapidly to be prevented by a pharmacologic
species is blocked. Importantly, the protective effect of agent [12].
dexrazoxane against the cardiotoxicity of anthracycline Studies performed several years ago by Fahey et al.
drugs occurs without affecting their antitumor activity. have shown that the net charge of thiol compounds with
This may be due, in part, to differences in the intracellular putative cytoprotective activity (table 1) markedly in-
0.1
0.1
60
Co γ - radiation
60
Co g-radiation WR - 1065 after 60
Co γ - radiation
WR-1065 before Co γ-radiation
60
0.01
0.01 100 b
80
60
60
HPRT
40 40
20 20
0 0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
60
Co g dose (Gy) 60
Co γ dose (Gy)
Fig. 2. Response to varying doses of 60Co Á-radiation of V79 Chinese Fig. 3. Response to varying doses of 60Co Á-radiation of V79 Chinese
hamster lung fibroblast cells in the absence or presence of WR-1065 hamster lung fibroblast cells exposed immediately after irradiation to
4 mmol/l added to cell cultures 30 min before irradiation and allowed WR-1065 4 mmol/l added to cell cultures and allowed to remain for
to remain until 3 h after irradiation. a Surviving fraction of cells. 3 h. a Surviving fraction of cells. b Mutation induction at the HPRT
b Mutation induction at the HPRT (hypoxanthine-guanine phospho- (hypoxanthine-guanine phosphoribosyl transferase) locus among sur-
ribosyl transferase) locus among surviving cells that were grown in a viving cells (assessed as described in fig. 2). The broken lines repre-
non-selective medium for 6 days and then exposed to 6-thioguanine sent the radiation-only curves and are presented for comparison.
5 Ìg/ml in ·-MEM-10 medium (containing hypoxanthine, aminop- Bars represent the standard errors of the mean of two or more repli-
terin and thymidine) for 7 days and stained with 0.5% methylene cate experiments (reproduced with permission from Grdina et al.
blue. Bars indicate the standard errors of the mean of two or more [15]).
replicate experiments (reproduced with permission from Grdina et
al. [15]).
fluences the degree of protection that they provide against Protective Effect of WR-1065 (Amifostine Metabolite)
the DNA-damaging effects of radiation [13, 14]. Because Studies in our institution using V79 Chinese hamster
WR-1065 has a net charge of +2, it will be attracted to lung fibroblast cells have shown that WR-1065 in a con-
DNA (which is negatively charged) and is therefore more centration of 4 mmol/l protects against radiation-induced
likely to exert a protective effect against radiation- cell death when added to cell cultures 30 min before var-
induced damage than a compound with a net charge of 0 ious doses of 60Co Á-radiation, but not when it is added
or a negative net charge. Evidence in support of this immediately after irradiation (fig. 2a, 3a). This treatment-
hypothesis has come from studies with WR-1065, capto- schedule dependence in the protective effect of WR-1065
pril, and N-acetylcysteine in Chinese hamster lung fibro- is to be expected if it is acting as a free radical scavenger,
blast and ovary cells. since protection could only be expected to occur when the
compound is present during irradiation [15].
10 -1
Radiation only
10 -2 Radiation +
4 mmol/l N-acetylcysteine
Without captopril Radiation +
0.04 mmol/l N-acetylcysteine
With 1 mmol/l captopril
10 -2 10 - 3
0 200 400 600 800 1,000 0 200 400 600 800 1,000
60
Co γ dose (cGy) 60
Co γ dose (cGy)
Fig. 4. Surviving fractions of Chinese hamster ovary (CHO)-AA8 Fig. 5. Surviving fractions of Chinese hamster ovary (CHO)-AA8
cells exposed to varying doses of 60Co Á-radiation in the absence or cells exposed to varying doses of 60Co Á-radiation in the absence or
presence of captopril 1 mmol/l added to the cell cultures 30 min prior presence of N-acetylcysteine 0.04 mmol/l and 4 mmol/l added to the
to irradiation (Grdina DJ, unpubl. data). cell cultures 30 min prior to irradiation (Grdina DJ, unpubl. data).
As well as increasing the surviving fraction of cells of a protective effect against radiation-induced cell killing
when administered before irradiation, WR-1065 has also with either drug (fig. 4, 5) [Grdina DJ, unpubl. data].
been shown to reduce the degree of radiation-induced Thus, key factors governing the radioprotective effica-
mutagenesis in V79 Chinese hamster lung fibroblast cells cy of a drug acting as free radical scavenger are: (1) an
(expressed as the HPRT mutant frequency per 106 survi- ability to concentrate within the nucleus or microenviron-
vors exposed to 6-thioguanine 5 Ìg/ml) (fig. 2b). In con- ment of DNA (dependent on its net charge), and (2) the
trast to the treatment-schedule dependence for the protec- presence of the protectant at the radiation target at the
tive effect against cell killing, the antimutagenic effect of time it is irradiated (important for prevention of cell
WR-1065 is also observed when it is administered after death). No clinical advantage is achieved if the protector
irradiation (fig. 3b), indicating that its post-irradiation does not differentially protect normal tissues compared to
action can effectively alter mutation induction in surviv- tumor.
ing cells [16].
70 (98)
Percent survival
60
50 Total No.
Fig. 7. Percentages of survivors over a peri-
Events of patients
od of 27 months among patients with pre- 40 Amifostine + radiotherapy 34 153
viously untreated head and neck squamous
30 Radiotherapy alone 45 180
cell carcinomas who were randomized to
receive either amifostine (200 mg/m2 i.v. 20
Log-rank: p = 0.184
over 3 min) 15–30 min before radiotherapy Hazard ratio: 1.351 (95% Cl 0.865 - 2.109)
doses of 1.8–2 Gy/day for 30 to 35 fractions 10
(total 54–70 Gy) or similar doses of radio- 0
therapy alone. The numbers of patients at
0 3 6 9 12 15 18 21 24 27
risk at 12 and 18 months are indicated in Months
parentheses (reproduced with permission
from Brizel et al. [18]).
ference between the two groups in locoregional tumor lung cancer and reduction of toxicities associated with
control rates. Thus, amifostine significantly reduced acute doxorubicin- and paclitaxel-containing regimens, high-
and chronic xerostomia in these patients without com- dose chemotherapies, and multimodality chemotherapy
promising the antitumor effectiveness of radiotherapy and radiotherapy for a variety of solid tumors. Possible
[18]. prevention of secondary tumors (see above), is also being
explored. In addition, the observation that amifostine
may stimulate bone marrow progenitor cells has led to
Potential Future Applications of Amifostine studies of its use as a potential treatment for patients with
myelodysplastic syndrome. As yet, however, clinical data
Other potential roles for amifostine that are being are limited and its value in this setting remains to be clari-
explored include reducing renal toxicity associated with fied [6].
cisplatin treatment in ovarian cancer and non-small-cell
References
1 Curran WJ: Radiation-induced toxicities: the 8 Safra T, Muggia F, Jeffers S, Tsao-Wei DD, 12 Hall EJ: Radiobiology for the radiologist, ed 5.
role of radioprotectants. Semin Radiat Oncol Groshen S, Lyass O, Henderson R, Berry G, Philadelphia, Lippincott Williams & Wilkins,
1998;8(4 suppl 1):2–4. Gabizon A: Pegylated liposomal doxorubicin 2000.
2 Brizel DM: Future directions in toxicity pre- (doxil): reduced clinical cardiotoxicity in pa- 13 Zheng S, Newton GL, Gonick G, Fahey RC,
vention. Semin Radiat Oncol 1998;8(4 suppl tients reaching or exceeding cumulative doses Ward JF: Radioprotection of DNA by thiols:
1):17–20. of 500 mg/m2. Ann Oncol 2000;11:1029– relationship between the net charge on a thiol
3 Schuchter LM: Current role of protective 1033. and its ability to protect DNA. Radiat Res
agents in cancer treatment. Oncology (Hun- 9 Wiseman LR, Spencer CM: Dexrazoxane: a 1988;114:11–27.
tingt) 1997;11:505–512, 515–518. review of its use as a cardioprotective agent in 14 Zheng S, Newton GL, Ward JF, Fahey RC:
4 Hoekman K, van der Vijgh WJF, Vermorken patients receiving anthracycline-based chemo- Aerobic radioprotection of pBR322 by thiols:
JB: Clinical and preclinical modulation of che- therapy. Drugs 1998;56:385–403. effect of thiol net charge upon scavenging of
motherapy-induced toxicity in patients with 10 Hasinoff BB: The iron(III) and copper(II) com- hydroxyl radicals and repair of DNA radicals.
cancer. Drugs 1999;57:133–155. plexes of adriamycin promote the hydrolysis of Radiat Res 1992;130:183–193.
5 Links M, Lewis C: Chemoprotectants: A re- the cardioprotective agent ICRF-187 ((+)-1,2- 15 Grdina DJ, Nagy B, Hill CK, Wells RL, Perai-
view of their clinical pharmacology and thera- bis(3,5-dioxopiperazinyl-1-yl)propane). Agents no C: The radioprotector WR1065 reduces ra-
peutic efficacy. Drugs 1999;57:293–308. Actions 1990;29:374–381. diation-induced mutations at the hypoxan-
6 Culy CR, Spencer CM: Amifostine: an update 11 Koning J, Palmer P, Franks CR, Mulder DE, thine-guanine phosphoribosyl transferase locus
on its clinical status as a cytoprotectant in Speyer JL, Green MD, Hellmann K: Cardio- in V79 cells. Carcinogenesis 1985;6:929–931.
patients with cancer receiving chemotherapy or xane – ICRF-187 towards anticancer drug 16 Grdina DJ, Shigematsu N, Dale P, Newton
radiotherapy and its potential therapeutic ap- specificity through selective toxicity reduction. GL, Aguilera JA, Fahey RC: Thiol and disul-
plication in myelodysplastic syndrome. Drugs Cancer Treat Rev 1991;18:1–19. fide metabolites of the radiation protector and
2001;61:641–684. potential chemopreventive agent WR-2721 are
7 Schuchter LM: Guidelines for the administra- linked to both its anti-cytotoxic and anti-muta-
tion of amifostine. Semin Oncol 1996;23(4 genic mechanisms of action. Carcinogenesis
suppl 8):40–43. 1995;16:767–774.
14%
10
4%
0
Pre-radiotherapy During radiotherapy Post-radiotherapy
Time relative to radiotherapy
Fig. 2. Disease-free survival among patients with squamous cell car- Fig. 3. Percentages of prostate cancer patients with fatigue ratings
cinoma of the glottic and supraglottic regions treated with primary greater than 5 (on a scale of 0–10) before, during and after radiother-
radiotherapy (60–70 Gy in 30–35 fractions over 6–7 weeks) in rela- apy in relation to whether they were anemic (Hb level ! 12 g/dl) or
tion to their hemoglobin (Hb) levels at day 35 of treatment. p Values not anemic at the time (Harrison LB, unpublished data). * Statistical-
indicate differences between disease-free survival in each group for ly significant versus non-anemic patients (p = 0.015).
patients with normal vs below normal Hb levels. Normal Hb values
were defined as 13.7–18 g/dl (8.5–11.0 mmol/l) for men and 12–
16 g/dl (7.5–10.0 mmol/l) for women (reproduced with permission
from van Acht et al. [11]).
Table 1. Influence of anemia on locoregional tumor control rates and survival rates in two studies in patients with
squamous cell carcinomas of the glottic larynx (n = 109) or head/neck region (n = 504) [9, 10]
a Hemoglobin ! 13 g/dl.
b Hemoglobin ! 13 g/dl (women) or ! 14.5 g/dl (men).
* p ! 0.01 vs anemic patients; ** p ! 0.001 vs anemic patients; NR = not reported.
one such outcome that has been strongly associated with in those who were anemic (hemoglobin !12 g/dl) than in
anemia [12–14]. In a group of patients with prostate can- those who were not anemic (fig. 3). This finding is of
cer treated with radiotherapy at our institution, the per- interest because fatigue is generally not considered a prob-
centage with a fatigue rating 15 (on a scale of 0–10) fol- lem in prostate cancer patients receiving radiotherapy
lowing radiotherapy was found to be significantly higher alone.
63%
55% 32%
60
Fig. 4. The prevalence of anemia (Hb ! 12 44% 45% 44%
g/dl) before and during radiotherapy in pa- 40 16%
tients with different types of cancer treated 26%
at the Department of Radiation Oncology,
20
Beth Israel Medical Center/St Luke’s-Roo- 9%
sevelt Hospital Center, New York between
December 1996 and June 1999. Baseline 0
Breast Colorectal Lung/ Prostate Uterine/ Head/
was defined as within 4 weeks prior to the cancer cancer bronchus cancer cervical neck
first radiation dose. During therapy was de- (n = 81) (n = 64) cancer (n = 90) cancer cancer
(n = 64) (n = 53) (n = 68)
fined as within 3 to 5 weeks of the first radia-
tion dose.
1.6 ]
radiation [15]. The prevalence of anemia was higher in
1.4
women than in men (54 vs 28% at baseline; 63 vs 43%
1.2 ]
during radiotherapy), and was higher in patients with cer-
1.0
tain types of cancer than others (fig. 4). In particular, high
0.8
0.6
prevalences of anemia were noted in patients with colo-
0.4
rectal, lung/bronchus and uterine/cervical cancers, and
0.2
increases in prevalence from baseline to end of therapy
0 were most notable for those with colorectal and lung/
Breast Colorectal Lung Prostate Cervical Head/ bronchus cancers (fig. 4). Among patients who experi-
cancer cancer cancer cancer cancer neck
(n = 71) (n = 48) (n = 101) (n = 78) (n = 48) cancer enced a drop in their hemoglobin level during radiothera-
(n = 86)
py, the mean decreases ranged from 0.75 g/dl for those
with breast cancer to 1.8 g/dl for those with head or neck
Fig. 5. Mean decreases in hemoglobin (Hb) levels during radiothera- cancers, and the decreases were statistically significant
py versus preradiotherapy in patients treated at the Department of (p ! 0.001) in all groups except those with breast and cer-
Radiation Oncology, Beth Israel Medical Center/St Luke’s-Roosevelt
vical cancer (fig. 5).
Hospital Center, New York between December 1996 and June 1999.
Data shown are for patients whose Hb levels decreased during treat- When the prevalence of anemia for each cancer type
ment. * Statistically significant difference versus baseline (p ! was stratified by the hemoglobin level measured at base-
0.001). line and the lowest level recorded during radiotherapy,
most patients in each group were found to have mild ane-
mia (hemoglobin levels 610 g/dl), which should be easily
correctable. These data, and the findings of studies re-
Prevalence of Anemia in Patients Undergoing viewed previously in this article indicating that the pres-
Radiotherapy for Various Cancers ence of anemia is associated with poorer treatment out-
comes, provide compelling evidence for employing strate-
Studies of patients presenting for radiotherapy at our gies to correct anemia and/or the resultant tumor hypoxia
institution between December 1996 and June 1999 (n = in cancer patients undergoing radiotherapy.
574) have revealed a high prevalence of anemia (hemoglo-
bin !12 g/dl) both before and during irradiation. Overall,
40 80 75% 75%
69%
Patients (%)
20 62% 62%
60 55%
50%
0
0 1 2 3 4 5 40
Years
20
* p (0.001 compared with group 2; ** p ! 0.05 compared with group 2; Hb = hemoglobin; SC = subcutaneously.
a Complete responses were determined by histopathologic analysis of the en bloc resection of the primary tumor and
regional cervical lymphatics performed 5 to 6 weeks after the completion of chemoradiotherapy.
b Dosage: 10,000 IU/kg SC 3 to 6 times per week until week of surgery.
daily on 5 days per week for 7 weeks) in patients with therapy in our earlier study of the prevalence of anemia in
locally advanced head or neck cancer. Anemic patients patients with various malignancies (fig. 5).
also received either blood transfusions or epoetin alfa to The effects of epoetin alfa on the outcomes of therapy
correct the anemia. Patients who breathed carbogen have been studied in anemic patients (Hb !14.5 g/dl)
4 min before and during irradiation exhibited improved with squamous cell carcinomas of the oral cavity or oro-
local control, cause-specific survival, and overall survival pharynx [23, 24]. All patients in this study received a regi-
at 18 months in comparison with a similar number of men consisting of mitomycin C (15 mg/m2 on day 1), 5-
patients who received the same chemoradiotherapy regi- fluorouracil (750 mg/m2 on days 1–5) and radiotherapy
men without carbogen breathing (fig. 7). The high re- (50 Gy in 25 fractions during weeks 1–5), followed by dis-
sponse rates achieved in this study appeared to persist as section of the primary tumor bed and a neck dissection.
the estimated probabilities of local control, cause-specific Epoetin alfa (10,000 IU/kg subcutaneously 3 to 6 times
survival, and overall survival at 3 years in the carbogen per week until the week of surgery) was administered to a
breathing group were similar to the rates observed at 18 group of patients (n = 57) who had a pretreatment hemo-
months [18]. globin level !14.5 g/dl. The outcome in this group of
patients was compared with the outcomes in two other
Epoetin Alfa (Recombinant Human Erythropoietin; groups who did not receive epoetin alfa. One of these non-
r-HuEPO) epoetin alfa groups had a pretreatment hemoglobin level
The ability of epoetin alfa to correct anemia prior to !14.5 g/dl (n = 87) and the other had a pretreatment
and during radiotherapy has been evaluated in cancer hemoglobin level 614.5 g/dl (n = 43). The results are
patients to determine whether it produces clinically summarized in table 2. In the two groups of patients who
meaningful benefit. Studies in patients receiving radio- did not receive epoetin alfa, those with a low pretreatment
therapy for various malignancies have shown that the hemoglobin level (!14.5 g/dl) (group 2) exhibited signifi-
administration of epoetin alfa, with or without oral iron, cantly lower complete response rates, 2-year locoregional
is effective in increasing hemoglobin levels and is well tol- control rates, and 2-year survival rates than those who
erated [19–21]. A study in our institution in cancer had normal hemoglobin levels (614.5 g/dl) (group 1).
patients receiving a variety of different chemotherapy reg- However, in the patients with a low pretreatment hemo-
imens with concomitant or sequential radiotherapy has globin level who received epoetin alfa (group 3), the rates
shown that weekly epoetin alfa administration improved of complete response, 2-year locoregional control and 2-
the mean hemoglobin level by 1.8–3.4 g/dl [22] (fig. 5). year survival were equivalent to or higher than those in
Improvements of this magnitude are similar to or greater patients with normal pretreatment hemoglobin levels
than the reductions in hemoglobin noted during radio- (group 1) [24].
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survival of T1–T2 squamous cell carcinomas of creases hemoglobin in cancer patients during Lanerolle NC, Cerami C, Itri LM, Cerami A:
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Proc Natl Acad Sci USA 2000;97:10526–
10531.
Abstract
Although the association between low hemoglobin lev-
els and poorer outcomes in radiation oncology has long Introduction
been recognized, anemia is often overlooked and un-
treated. However, a growing body of clinical evidence In radiation oncology, it is widely accepted that tumor
now indicates that low hemoglobin levels during radia- hypoxia causes radiation resistance. Anemia is also asso-
tion treatment are associated with decreased response ciated with poorer outcomes to radiation. It has been
and survival following radiotherapy. For example, a inferred that there is a causal relationship between low
large Canadian retrospective study in patients receiving hemoglobin levels, the resulting hypoxia and a poor out-
radical radiotherapy for cervical cancer showed that the come of radiotherapy in patients with cancer.
5-year survival rate was 19% higher in those whose Even though hemoglobin levels are monitored at most
hemoglobin during radiation treatment was =12 g/dl radiation oncology centers, anemia is often overlooked by
compared to those with levels ! 12 g/dl. The data suggest radiation oncologists and is frequently only treated if
that clinical trials need to be performed to determine severe. It has been suggested that oncologists do not rou-
whether increasing hemoglobin levels leads to improved tinely treat mild-to-moderate anemia as it is perceived to
local control and survival. The mechanism by which low be clinically unimportant [1] and that patients are often
hemoglobin levels could cause poorer outcomes is not not transfused unless hemoglobin levels fell below 10 g/dl
well understood and needs further elucidation. It is pos- or even 8 g/dl [1, 2]. For example, a US study in 1987
tulated that lower hemoglobin levels resulting in de- showed approximately two-thirds of academic radiation
Survival
Significant
Stage 0.0001 0.4
Average weekly nadir hemoglobin level 0.0001
Intracavitary treatment 0.0004 0.2 p <0.003
Squamous histology 0.0446
0.0
Nonsignificant 0 1 2 3 4 5 6
Age Year
Presenting hemoglobin level
Radiation dose
Center
Fig. 1. Survival in patients with carcinoma of the cervix receiving
Transfusion
radiotherapy stratified according to hemoglobin level (Hb) at presen-
Transfusion year
tation (reproduced with permission from Grogan et al. [4]).
Treatment volume
Treatment time
Chemotherapy
1.0
0.8
— L – H (n = 25)
— H – H (n = 228)
limit of the normal range for women). Despite this, only
0.6
Survival
0.8 Hb
NT
12.0 g/dl
T
0.6
Survival
NT
11.0–11.9 g/dl
T
0.4
NT
<11.0 g/dl
T
0.2 p <0.0001
Fig. 3. Survival in patients with carcinoma
of the cervix according to transfusion status
0.0
and average weekly nadir hemoglobin levels 0 1 2 3 4 5 6
(Hb) during radiotherapy, where T = trans- Year
fused and NT = not transfused (reproduced
with permission from Grogan et al. [4]).
(table 2). Initial hemoglobin levels were not significant show that it is the hemoglobin level attained, rather than
suggesting that the effect of low presenting hemoglobin the use of blood transfusions, that influenced outcome in
levels could be overcome by raising the level during treat- these patients. It also confirmed the prognostic signifi-
ment. cance of hemoglobin levels during radiotherapy [4].
To further examine the differential impact of low It was concluded from the Canadian study that the
hemoglobin levels during treatment versus those at pre- hemoglobin level during radiotherapy is an important
sentation, the survival data were reanalyzed according to prognostic factor, second only to disease stage, in patients
hemoglobin levels both at baseline and during radiothera- with cervical cancer. The survival data from this study
py (fig. 2; n = 475). The analysis showed that patients who generate the hypothesis that maintaining hemoglobin lev-
had low hemoglobin levels during radiotherapy, regard- els above 12 g/dl in patients with cervical cancer can
less of their baseline hemoglobin levels, had a significantly improve the response to radiotherapy. The study further
poorer rate of survival than those whose hemoglobin lev- showed that the mechanism by which hemoglobin levels
els were maintained greater than 12 g/dl during radiother- are maintained (i.e., transfusion) is not important, but
apy (fig. 2). The 5-year survival rates for those with low rather the hemoglobin level that is attained during radio-
hemoglobin levels during radiotherapy were 51% or less therapy.
compared with rates of at least 70% in patients who had
high hemoglobin levels during radiotherapy (fig. 2). The Concurrent Radiotherapy and Chemotherapy
relapse rates in patients with low hemoglobin levels dur- Since the study by Grogan et al. [4] was completed,
ing radiotherapy (56 and 60%) were almost double those concurrent cisplatin-based chemotherapy and radiothera-
of patients with high hemoglobin levels during therapy py has emerged as the treatment of choice for patients
(32 and 33%). Interestingly, patients with high hemoglo- with advanced cancer of the cervix [6] as for many other
bin levels during radiotherapy also showed significant epithelial cancers.
reductions in both pelvic (p ! 0.0001) and extrapelvic fail- A recent study by Pearcey et al. [7], however, showed
ure rates (p ! 0.0006) [4]. no benefit for the addition of concurrent cisplatin to
Finally, the study examined whether raising hemoglo- radiation. Contrary to the previous trials in patients with
bin levels with blood transfusions influenced the outcome cervical cancer, which demonstrated a survival benefit for
of radiotherapy (fig. 3). A significant stepwise increase in chemoradiotherapy versus radiotherapy alone [8–12],
overall survival was observed with increasing hemoglobin Pearcey et al. [7] observed similar 3- and 5-year survival
levels during radiotherapy (fig. 3; p ! 0.0001). Survival rates with concurrent cisplatin and radiotherapy versus
rates were not significantly different between patients radiotherapy alone in patients with advanced cervical car-
who attained a given hemoglobin level spontaneously and cinoma. While there are many possible explanations for
those who received blood transfusions (fig. 3). These data the lack of benefit observed with chemoradiotherapy in
this trial, one reason may have been a differential drop in therapy in a cancer type other than cervical cancer. Some
hemoglobin levels during therapy (fig. 4) between treat- have postulated that the poor results in anemic patients
ment groups. As would be expected, decreases in hemo- are a result of the association between anemia and large
globin levels were found to be significantly greater in tumor volumes and development of distant metastases.
patients receiving chemotherapy plus radiotherapy versus Since laryngeal cancer does not have these characteristics,
those receiving radiotherapy alone (fig. 4). Thus, is it pos- these data add weight to the suggestion that the relation-
sible that the decreases in hemoglobin levels during thera- ship between anemia and outcome is not solely tumor-
py abrogated the beneficial effects of chemotherapy in related; the hypothesis generated is that some decrement
this study. in response to therapy may occur if the hemoglobin level
is low during treatment.
rate in patients who had hypoxic tumors compared with Table 4. Molecular events linking hypoxia and angiogenesis [25]
those whose tumors were oxygenated (table 3).
Hypoxia-regulated genes (e.g., VEGF, EPO, LDHA, Glut-1)
It has long been recognized that hypoxia adversely
HIF-1· mediates transcriptional response by binding to the hypoxia
affects the sensitivity of tumor cells to many chemothera- responsive elements of genes
peutic agents. Although the precise mechanisms are un- HIF-1· induces VEGF and increases expression and half-life of
known, oxygen is a radiosensitizer and impairs the ability mRNA
to repair DNA damage caused by radiation-induced free Hypoxia leads to loss of p53, increases VEGF and decreases TSP-1
H-ras and V-src (oncoproteins) amplify response to hypoxia and
radicals.
lead to increased VEGF and decreased TSP-1
More recently, attention has focused on the ability of
tumor hypoxia to enhance malignant progression. This is EPO = erythropoietin; HIF-1a = hypoxia-inducible factor 1a;
based on the findings of Höckel et al. [17] who showed LDHA = lactate dehydrogenase A; TSP-1 = thrombospondin-1;
that, following tumor resection in 47 patients with cervi- VEGF = vascular endothelial growth factor.
cal cancer, hypoxic tumors had larger extensions, more
frequent parametrial spread and lymph-vascular involve-
ment compared with oxygenated tumors. It is thought
that hypoxia may drive disease progression through clonal
selection and genome changes (for review see Höckel & although the available data are limited. Obermair et al.
Vaupel 2001) [22], which in turn produces a growth [26] used microvessel density count as a measure of angio-
advantage for tumor cells that are resistant to apoptosis. genesis in patients with stage IB cervical cancer who
Hypoxic tumors may overexpress the suppressor gene underwent surgery. They found that the 5-year overall
p53, a phenotype with a high malignant potential [23]. survival rate was significantly better in patients with a
Hypoxia may also induce changes within the tumor microvessel density of 20/field (n = 102) than in those
cells for the expression of oxygen-dependent proteins, with higher microvessel densities (n = 64) (80.7 versus
such as vascular endothelial growth factor (VEGF), which 63.0%; p ! 0.0001).
stimulate angiogenesis and increase the potential for tu- More recently, Birner et al. [27] showed that the
mor growth and metastases [24]. expression of hypoxia-inducible factor 1a (HIF-1a), a
transcriptional factor that promotes angiogenesis and reg-
ulates genes involved in the response to hypoxia, in-
Effect of Angiogenesis on Treatment Outcome fluenced prognosis in 91 surgically-treated patients with
stage I cancer of the cervix. Once again, patients with
Angiogenesis, the growth of new capillary vessels sup- strong expression of HIF-1a had a significantly poorer
porting tumor growth and progression, is stimulated by overall survival (p = 0.03) and disease-free survival (p !
hypoxia. A summary of molecular events linking angio- 0.0001) compared with those with moderate or no expres-
genesis with intratumoral hypoxia is provided in table 4 sion of HIF-1a.
[25]. Like hypoxia, angiogenesis has also been shown to
influence outcome to surgery in patients with cancer,
Anemia, Hypoxia and Angiogenesis: Are They type and individual patient physiology, may also be in-
Linked? volved.
The relationship between anemia and angiogenesis
While there is evidence to suggest a direct association remains poorly understood and data are sparse. A Ger-
between hypoxia and angiogenesis, less is known about man group [30] showed that there was a trend towards
how anemia is linked to hypoxia and angiogenesis (fig. 5). higher serum VEGF levels in cancer patients with low
Anemia may exacerbate intratumoral hypoxia by lower- hemoglobin levels undergoing radiotherapy, suggesting
ing the oxygen carrying capacity of the blood, although the that anemia may stimulate angiogenesis via hypoxia. Pa-
link between the two and its relevance in the clinical set- tients had previously untreated, non-metastatic gyneco-
ting remain controversial [1]. Nordsmark et al. [28] in logic cancer (n = 22), head and neck cancer (n = 14), gas-
Denmark recently showed that there was no relationship trointestinal cancer (n = 13), lung cancer (n = 4) and pros-
between hemoglobin levels and pretreatment tumor oxy- tate cancer (n = 1). In 26 patients with hemoglobin levels
gen partial pressure in 263 patients with head and neck of !13 g/dl, mean serum VEGF levels were 805,656 pg/ml
carcinoma. However, both hemoglobin levels and tumor compared with levels of 438,360 pg/ml in 28 patients with
oxygenation status (pO2 fraction !2.5 mm Hg) were inde- hemoglobin levels of 113 g/dl (p = 0.016) [30].
pendent prognostic factors for overall survival. Likewise
Brizel et al. [29] noted only a weak association between
low hemoglobin levels and poor tumor oxygenation status Correcting Hemoglobin Levels
in patients with head and neck cancer receiving primary
radiotherapy; many patients with higher hemoglobin lev- There are several potentially reversible causes of ane-
els (= 13 g/dl) also had hypoxic tumors. These data suggest mia (such as nutritional deficiencies, chronic blood loss,
that low hemoglobin levels and tumor hypoxia may be and subclinical disseminated intravascular coagulopa-
linked in a complex fashion but other factors, tumor thy), which should be sought and, if possible, corrected in
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Angiostatin
Novel Systemic Agents Undergoing Testing in In a recent phase I trial at Jefferson Medical College in
Chemoradiotherapy Regimens Philadelphia involving a small number of patients with
advanced cancer of the head and neck, prostate, breast,
Substantial gains have been made over the past several and lung, it was determined that the combination of
years in the induction of remissions with the use of che- angiostatin (an antiangiogenesis drug that has antitumor
moradiation therapy. Despite these advances, patient sur- activity) plus radiotherapy is well tolerated and partial
vival rates are still unacceptably low and new treatment local responses were observed. Studies are ongoing to
strategies are needed. Several promising, novel systemic evaluate longer-term treatment at higher doses [26].
agents are currently undergoing evaluation for use in con-
junction with RT. Farnesyl Transferase Inhibitors
Farnesyl transferase inhibitors target the protein en-
Cyclooxygenase-2 Inhibitors coded by the ras oncogene, blocking its membrane anchor-
Cyclooxygenase (COX) catalyzes the synthesis of pros- age, and thereby inhibiting its cell transforming ability [27].
taglandins from arachidonic acid. One form of the en- R11577 is a potent and selective farnesyl transferase inhib-
zyme, COX-2, is overexpressed in a variety of different itor that has shown antitumor activity in animal models,
CALGB = Cancer and Leukemia Group B; ECOG = Eastern Cooperative Oncology Group; EGFR = Epidermal
growth factor receptor; N2 = mediastinal lymph node metastasis; NSCLC = non-small-cell lung cancer; RT = radio-
therapy; RTOG = Radiation Therapy Oncology Group; SWOG = Southwest Oncology Group.
Table 2. Evidence for improvement over time in the treatment of Table 3. Concurrent vs. sequential chemoradiotherapy for NSCLC –
unresected NSCLC impact on median survival time
Cooperative Group Trial Median survival 3-year Study Median survival time (months)
time (months) survival
concurrent sequential p value
CALGB 8433 RT [1] 9.6 10%
Curran et al. [10] 17.1 14.6 0.03998
CALGB 8433 sequential CRT [1] 13.7 24%
Furuse et al. [29] 16.5 13.3 0.038
RTOG 9104 concurrent CRT 19.6 40%
RTOG 9410 sequential CRT [2] 14.6 31%
NSCLC = Non-small-cell lung cancer.
RTOG 9410 concurrent CRT [2] 17.0 37%
SWOG 9504 concurrent CRT [28] 27 140%
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