Sparing pelvic bone marrow using different radiotherapy techniques in patients receiving concurrent chemo radiation for carcinoma cervix
and arriving at a viable therapeutic predictor.
A dissertation submitted to
The Tamilnadu Dr. M.G.R. Medical University, Chennai, In partial fulfilment of the requirements for the award of
The degree of
DOCTOR OF MEDICINE (M.D.) IN RADIOTHERAPY April 2012
This is to certify that this dissertation titled, “Sparing pelvic bone marrow using different radiotherapy techniques in patients receiving concurrent chemo radiation for carcinoma cervix and arriving at a viable therapeutic predictor” is a bonafide record of the work done by Dr. Vasanth Christopher Jayapaul.C, in the Division of Radiation Oncology, Cancer Institute (W. I. A.), Chennai, during the period of her postgraduate study for the degree of M.D. (Branch IX – Radiotherapy) from 2009-2012 under my direct guidance and supervision.
Date: Dr.G. Selvaluxmy,
Place: Chennai Professor and Head of Department,
Division of Radiation Oncology, Cancer Institute (W.I.A.),
A patient with locally advanced carcinoma breast, detected to have carcinoma cervix, was referred for cervical cancer treatment after initial chemotherapy. When we are discussing the plan of treatment, we are very wary about the neutropenia, due to pelvic radiation. Then we had a look in the literature and found many bone marrow sparing techniques and normal tissue complication probability for bone marrow toxicity. The search of cost effective bone marrow sparing technique for this patient is the first seed for the start of this study. Thus we were able to work with our physicists to generate many plans for a single patient, and then we systematically analyzed the same in 44 patients. I am grateful to Dr. Selvaluxmy, professor, Head of Department, who is the main source of inspiration for this study, her experience coupled with her novel ideas, made this study possible. I also thank Dr.Vasanthan, Chairman of Division of Radiation oncology, who motivated in shaping out the study. I also thank Dr.
Selvarani, senior resident, who constantly helped me in this study. I am very grateful to Mr.Prabakaran, medical physicist, who helped in planning of these treatment techniques. I thank all my teachers Dr.Faith Vishwanathan, Dr.Alexander, Dr.Satish Srinivas, Dr.Ananthi, Dr.Arun kumar, who were always the source of motivation. I express my gratitude to all my colleagues, my family, staffs and technicians who were with me, and morally supported me in this study.
I am ever thankful to all patients who were a part of this study, and pray for their speedy recovery to their normal life. I thank Almighty, Whose love on me, helped me to respect others love and to love all equally.
TABLE OF CONTENTS
1) Evolution of cervical cancer treatment 2
2) Cervical cancer epidemiology 4
3) Overview of treatment in cervical cancers 7
4) Concurrent chemo radiation in carcinoma cervix 12
5) Acute toxicity in chemo radiation 17
6) Bone marrow and chemo radiation 20
7) Imaging of bone marrow 25
II Objectives and methodology
1) Aim of the study 30
2) Specific objectives 31
3) Study design 32
4) Data collection 34
III Results and analysis 39
IV Discussion 51
V Conclusion 55
VI References 56
1) Evolution of cervical cancer treatment.
2) Cervical cancer epidemiology.
3) Overview of treatment in cervical cancers.
4) Concurrent chemoradiation in carcinoma cervix.
5) Acute toxicity in chemoradiation.
6) Bone marrow and chemoradiation.
7) Imaging of bone marrow.
EVOLUTION OF CERVICAL CANCER TREATMENT
Publication of the paper by Wilhelm Conrad Roentgen on December 28, 1895, describing the discovery of new rays, marked the dawn of radiation oncology. In 1896 nearly 1000 scientific papers and 50 books spoke about these wonder rays. Followed by the discovery of radioactivity by Becquerel, and radium by the Curies, the new modality of cancer treatment known as radiation therapy claimed its first apparent cure of skin cancer.
In 1902 X rays were used to treat cervical cancer, which was the first documented evidence. Albert Doderlein of Tubingen reported the first use of intra cavitary radium in 1903 for inoperable cervical cancer . Margaret Cleaves reported uses of intra cavitary radium treatment along with roentgen-rays for cervical carcinoma in 1903 . Then in October of 1903, William James Morton reported the use of a radium applicator “to be introduced within cavities where it has been heretofore impossible to practically introduce the X-ray” . Other reports of treatment of cervical carcinoma with intra cavitary radium followed during 1903-1905 in New York. In 1913, Robert Abbe was the first to record a true cure with a patient alive and well, eight years later .
In early years they had limited knowledge about the radiobiology and dose distribution in the tumour and surrounding normal tissues. Hence the dose was entirely empirical, so complications and failures were common.
In 1932 Paris system was defined and following that in 1938 Tod and Meridith defined the Manchester system, which was later modified in 1953 at the Holt Radium Institute & Christie Hospital . Manchester system standardised treatment with predetermined doses and dose rates directed to fixed points in the pelvis in an attempt to reduce the empiricism of the day and the existing high rate of complications.
In late 1940’s Gilbert Fletcher established the Fletcher (M.D.Anderson) system. It was the first effort to adopt three dimensional approach for dose distribution in the pelvis. He envisaged that better results and less morbidity can be obtained by knowing the dose absorbed in various points in the pelvis. His work mainly includes dose distribution analysis based on radiographs even in the pre-computer era .
The introduction of after loading applicators and computerised dosimetry brought a great change in treatment with brachytherapy. Both CT scan and MRI scan images can be used for planning. MRI based brachytherapy is gaining popularity due to better soft tissue delineation. Earlier four field box technique is the most popular technique for external beam radiotherapy. With the advent of 3D conformal radiation therapy, intensity modulated radiation therapy; we have succeeded to reduce the normal tissue toxicity.
Many attempts were made to improve the local control of disease. Studies on hyperthermia, hyperbaric oxygen, hypoxic cell sensitizers failed. But encouraging results with cisplatin has improved the local control and survival. PET CT imaging has revolutionized the field of oncology. In carcinoma cervix PET based planning was used to escalate dose to the para aortic nodes  and also used for better target delineation in brachytherapy.
Technology, newer therapeutic and imaging options have complemented the treatment of carcinoma cervix and also have raised many questions. The notable one is regarding the toxicity of normal tissues and the strategies of preventing the same, when treated with concurrent chemo radiation.
CERVICAL CANCER EPIDEMIOLOGY
Among the commonly diagnosed malignancies, cervical cancer ranks third and stands fourth for the most common cause of cancer deaths. Cervical cancer accounts for 9%
(529,800) of the total new cancer cases and 8% (275,100) of the total cancer deaths among females in 2008 . More than 85% of these cases and deaths occur in developing countries.
India, the second most populous country in the world, accounts for 27% (77,100) of the total cervical cancer deaths, accounting for 27 %( 1, 34,420) of the total new cases and 15.2 % (72,825) of the total cervical cancer deaths among females in 2008. The age-standardized rate per 100,000 person-years in Chennai, Tamil Nadu was 22.1 for the year 2006, based on data from the Madras Metropolitan tumour registry . The estimated age-standardized rate per 100,000 person-years in Chennai, Tamil Nadu for the year 2015 is 12. Thus it is estimated that there will be increase in the incidence of breast cancer and decrease in the incidence of cervical cancer .
In 1713, Bernardino Ramazzini, an Italian doctor, reported the absence of cancer cervix among nun sisters and wondered whether; this association is due to their celibate life. This observation was an important step toward identifying and understanding the importance of sexually-transmitted infections and cancer risk . In 1923, George Papanicolaou presented his research work in understanding the menstrual cycle. He recognised the ability of exfoliative cytology to detect cervical cancers, which then became the first screening test to be widely used . The high burden of cervical cancer in developing countries may be due to inability to develop, large scale screening programs, which will allow detection of premalignant and early cancer lesions.
The most efficient and cost-effective screening techniques in low-resource countries include visual inspection using either acetic acid or Lugol’s iodine and DNA testing
for human papilloma virus (HPV) DNA in cervical cell samples. A recent clinical trial in rural India, a low-resource area, found that a single round of HPV DNA testing was associated with about a 50% reduction in the risk of developing advanced cervical cancer and associated deaths .
The age of coitarche is the most important epidemiological factor. The risk of cervical malignancy increases 26 fold, when the first sexual intercourse was immediate year later to menarche, compared to 23 years. Human Papilloma virus (HPV) is the main causative agent for the development of cervical cancer. Persistent human papilloma virus infection will cause the progression of the premalignant lesion to invasive disease. Nearly half of the sexually active men and women contract HPV infection, but not all with infection develop disease. Only 3-10% women have persistent HPV infection and develop invasive malignancy. Among the several HPV strains HPV 16 and 18 accounts for 70% of all cervical cancer cases, other 5 strains 31, 33, 35, 45, 52 and 58 accounts for 20% of all cases. The global prevalence of HPV infection is 11.4%, which is 7.9% in India. The most important is the cofactors which would interact and cause persistent HPV infection. The notable cofactors are cigarette smoking, Chlamydia and HSV infection, influence of sex hormones, immunosuppression either in the form of acquired immunodeficiency or due to immunosuppression therapy and beta carotene deficiency.
In June 2006, the Food and Drug Administration (FDA) approved the first preventive HPV vaccine (quadrivalent HPV recombinant vaccine [Gardasil]). In 2007, the FDA approved a second HPV vaccine (HPV bivalent vaccine [Cervarix]), the vaccine showed 100% efficacy against cervical lesions and external anogenital and vaginal lesion in the patients who completed the vaccination regimen . Attention has returned to the role of herpes simplex virus type 2 (HSV2) as a potential cofactor with HPV in the initiation of malignant degeneration. Women with HSV2 alone have a 1.2 relative risk (RR) compared
with women negative for both HPV and HSV2. Those positive for HPV16/18 DNA alone had an RR of 4.3, but those positive for HPV 16/18 and HSV2 had an RR of 8.8 .
Diethylstilbestrol (DES), a nonsteroidal estrogen developed in the 1940s and used in the prevention of recurrent or threatened miscarriages, was administered to between 0.5 and 2 million women in the United States before it was banned for this purpose by the FDA in 1971. Intrauterine exposure to DES was found to be associated with the development of clear cell adenocarcinoma of the cervix and vagina .
In India, there is no specific national policy on cervical cancer control and prevention, and the National Cancer Control Programme does not have a specific cervical cancer component within it. Screening for cervical cancer takes place in an opportunistic manner, with cytology based screening facilities being available mainly at the tertiary level, where women are screened only at the most advanced stages of cancer, or if they visit the tertiary hospitals for reproductive tract infections .
Recently, a National Task Force was constituted for developing a “Strategy for Cancer Control in the 11th five year plan (2007-2011)”, which developed a report in March 2008, summarising the current scenario and developing a comprehensive cancer control strategy for the country. (NCCP Task Force Reports for XI Plan, 2008) .
The recommendations for cervical cancer are:
Opportunistic screening using sustainable and financially viable means.
Capacity building for early detection and diagnosis.
Development of infrastructure for appropriate treatment and regular follow up.
Provision of palliative care for advanced stage cancer across the country.
OVERVIEW OF CERVICAL CANCER TREATMENT
Figure 1: Treatment Algorithm of carcinoma uterine cervix Diagnosis of
Clinical and radiological staging
Radiacal hysterectomy with
pelvic nodal dissection
Radical Radiotherapy with
Radical hysterectomy with
Low risk – NO adjuvant treatment
Intermediate risk- Radiation only
High risk- Chemoradiation
chemoradiation Stage II.B- IV.A
Radical radiation with weekly
Extensive data support the theory that malignant lesions arise from the precursor lesions described as high grade squamous intraepithelial lesion.Once the disease has broken through the basement membrane, the possibility of metastatic spread exists.
Carcinoma of the cervix is divided into micro invasive or invasive. As disease progresses within the cervix, common symptoms of cervical pain, dyspareunia, vaginal discharge, or frank bleeding are reported.
Pain referred to the low back or gluteal region may be present, either because of locally aggressive disease or involvement of pelvic adenopathy with pressure on the lumbosacral nerves or hypogastric plexus.
Bleeding, from minor spotting to life-threatening hemorrhage, may occur. A prolonged history of intermittent bleeding may be associated with a significant anemia and depletion of iron stores in the marrow. Bleeding may be emergent in some cases and can be associated with small as well as large lesions.
Local progression of disease may result in invasion of surrounding organs.
Hematuria and dysuria secondary to bladder invasion, rectal pain, bright red blood per rectum or change of stool caliber caused by rectal involvement, or hydronephrosis and uremia secondary to ureteral obstruction by tumor may occur. The most common cause of death in advanced cervical cancer is renal failure.
In neglected cases, fistula formation may already be present with fecal or urinary diversion into the vagina. Fever secondary to local infection of the cervix, vagina, and vulva, or urinary tract infections with the possibility of pyelonephritis may be seen.
Treatment should involve close collaboration between the gynecologic oncologist and the radiation oncologist, with an integrated team approach vigorously pursued.
9 Carcinoma In Situ:
Patients with carcinoma in situ, which may include those with severe dysplasia, usually are treated with a total abdominal hysterectomy, with or without a small vaginal cuff. The decision to remove the ovaries depends on patient age and the status of the ovaries. Intracavitary irradiation (tandem and ovoids) may be useful for the treatment of in situ carcinoma, particularly in patients with strong medical contraindications for surgery or when there is multifocal carcinoma in situ in both the cervix and vagina .
Early invasive carcinoma of the cervix (stage IA2) usually is treated with a total abdominal or modified radical hysterectomy, but it can be treated with intracavitary radioactive sources alone.
Stages IB and IIA:
The choice of definitive irradiation or radical surgery for stage IB and IIA carcinoma of the cervix remains highly controversial, and the preference of one procedure over the other depends on the general condition of the patient and the characteristics of the lesion like presence of endocervical component and other risk factors . Tumor control and survival are equivalent with either modality.
Stages IIB, III, and IVA:
Patients with stage IIB and III tumours are treated with irradiation alone.
Patients with stage IVA disease (bladder or rectal invasion) can be treated either with pelvic exenteration, or with high doses of external irradiation to the whole pelvis, intracavitary insertions, and additional parametrial irradiation.
Concomitant use of irradiation and cisplatin, has been administered to obtain a radio sensitizing effect. Several randomized trials have shown improved outcome with concomitant irradiation and chemotherapy compared with irradiation alone. So it is always advisable to go for concurrent chemo radiation, in absence of contraindication to chemotherapy.
Adjuvant postoperative therapy:
The decision on adjuvant therapy following hysterectomy depends on the prognostic factors like status of the lymph nodes, size of the primary tumour, depth of stromal invasion, presence or absence of lymph-vascular space invasion, presence or absence of parametrial extension, histological cell type and status of the vaginal margins.
There were three independent prognostic factors:
The clinical size of the tumour.
The presence or absence of lymph-vascular space invasion.
The depth of tumour invasion.
The risk stratification is done by calculating the GOG score. The GOG score is calculated by multiplying the relative-risk for depth X tumour size X lympho vascular space involvement.
Low risk (GOG score less than 40) – No adjuvant therapy.
Intermediate risk (GOG score 40-120) – only radiation.
High risk (GOG score more than 120) – concurrent chemo radiation.
Risk factors Variables Relative risk Depth of penetration
Superficial 3 1.0
Middle 5 20
Deep 7 28
Clinical tumour size Occult 1.0
Table 1- Relative risks of the pathological factors. Adapted from Best Clinical Practice Gynaecology, 2009 guidelines. Greater metropolitan clinical taskforce.
CONCURRENT CHEMORADIATION IN CARCINOMA CERVIX
Both chemotherapy and radiation, have been used together to increase either mutual or simultaneous sensitization. The earlier notable example dates 100 years ago, when radiation treatment and systemic benzene treatment were combined for the treatment of leukaemia. In the late 1970’s Steel and Peckham developed a conceptual framework for analyzing drug-radiation interactions . In this seminal work, four mechanisms were described in which combined modality therapy could improve therapeutic outcome:
Protection of normal tissue, and
Enhancement of tumour response.
For more than 20 years, these mechanisms provided the backbone for evaluating chemo radiation combinations clinically. Based on lessons learned from these clinical investigations coupled with the rapid emergence of molecularly targeted agents, Bentzen and colleagues proposed an updated conceptual framework to evaluate drug-radiation combination .
One of the clearest clinical examples demonstrating improved outcomes of combined chemo radiation is in locally advanced cervical cancer. Radiation therapy was the single most effective modality for treatment of carcinoma cervix, either when surgical resection is not technically possible or when surgical resection is not medically feasible.
Many cases fail in the scenario of bulky local disease or regional metastatic disease. For the past 40 years many trials have been conducted to explore the agents which are likely to
increase the potential of cure in these patients. Initial studies evaluated the potency of hydroxyurea to increase the cure with radiation. Many studies found to have benefit, but a Cochrane review in 2004 proved that there is no evidence to support the use of hydroxyurea combined with radiation in the treatment of carcinoma cervix . Another cause for selective radio resistance, in large tumours was tissue hypoxia. Many studies combined radiation with hypoxic cell radio sensitizers like misonidazole, pimonidazole, but none proved the benefit of these agents in carcinoma cervix. With the observation from all these earlier trials, in 1996 the National Institutes of Health Consensus Statement on Cervical Cancer stated that there was “no proven benefit to combining chemotherapy with radiation”
in locally advanced cervical cancer .
From 1996 to 1999, a series of 5 phase three randomised clinical trials combining radiation with cisplatin revolutionized treatment of carcinoma cervix. Based on the results of these trials, in the second month of 1999, the National Cancer Institute (NCI) issued a clinical announcement stating that “strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.”
GOG 85 & SWOG 8695 Study- Charles W.Whitney et al:
Patients with stage IIB- IVA were randomised to receive hydroxyurea or cisplatin /5 flurouracil. There was a significant changes in 5-year progression free survival with cisplatin/5-Flurouracil (57% versus 47%) and overall survival at 5 years (62% versus 50%). Thus proving that cisplatin based regimen is superior compared to hydroxyurea.
GOG 120 study- Peter.G. Rose et al:
Patient with stage IIB–IVA were randomised either to weekly cisplatin alone or hydroxyurea alone or combination with cisplatin, 5-flurouracil and hydroxyurea. This study concluded that there is a significant survival benefit with cisplatin containing regimens.
3 year overall survival was 65% for platinum based arms versus 47% in non platinum based arm. This study also concluded that weekly cisplatin is effective and less toxic.
RTOG 90-01 protocol- Mitchell Morris et al:
Patients with stage IB–IVA were randomised to either pelvic radiation with cisplatin and 5-flurouracil versus pelvic with para aortic radiation. There was a significant difference in the 8 years disease free survival (61% with chemotherapy versus 46%) and overall survival (67% with chemotherapy versus 41%). Interestingly there was no change in the para aortic failure rates .
GOG 123 study- Henry M.Keys et al:
Women with bulky stage IB cervical cancers were randomly assigned to receive radiotherapy alone or in combination with cisplatin, followed in all patients by adjuvant hysterectomy. There was a significant change in 3-year progression free survival (79% with cisplatin versus 67%); 3- year overall survival (83% with cisplatin versus 74%).
The pathological complete response rates were also higher with cisplatin. This study concluded that weekly cisplatin is superior to radiation alone in bulky stage IB2 .
Intergroup 0107 (SWOG 8797/GOG 109/RTOG 91-12)- Pearcey et al:
Patients eligible for this intergroup study were those with stage IA2, IB, or IIA carcinoma of the cervix who was initially treated with radical hysterectomy and pelvic lymphadenectomy and who was found to have positive pelvic lymph nodes, positive margins, and/or positive parametrial infiltration on microscopic evaluation. They were randomised to either concurrent chemo radiation with cisplatin and 5-flurouracil or radiation alone. There was a significant difference in 4 year over all survival (81% with concurrent chemo radiation versus 71%) .
15 Overview of concurrent chemo radiation trials:
The five studies had different eligibility criteria, but in total included a broad spectrum of clinical presentations:
locally advanced tumours for which chemo radiation represented primary therapy,
bulky early-stage cancers in which chemo radiation was delivered prior to adjuvant hysterectomy, and
Post radical hysterectomy cases with high-risk pathologic factors for which adjuvant chemo radiation was given.
There was a consistent statistically significant survival advantage favouring the RT arm that included a concurrent cisplatin-based regimen, as compared with RT alone or RT combined with hydroxyurea, with a dramatic 30% to 50% decrease in the risk of death from cervical cancer. Several of these studies, have been updated and confirm that the statistically significant survival advantage of cisplatin basedchemo radiation is maintained over the long term, and they validate the 1999 NCI clinical alert.
In 2010, Cochrane gynaecological oncology group evaluated all concurrent chemo radiation trials. It is a review of twenty four trials (21 published, 3 unpublished) and 4921 patients and concluded, “Concomitant chemo radiation appears to improve overall survival and progression-free survival in locally advanced cervical cancer. It also appears to reduce local and distant recurrence suggesting concomitant chemotherapy may afford radio sensitisation and systemic cytotoxic effects. Some acute toxicity is increased, but the long- term side effects are still not clear.”
Table 2- Adapted from concomitant chemotherapy and radiation therapy for cancer of the uterine cervix (Review). Cochrane Database of Systematic Reviews, Issue 1,2010.
ACUTE TOXICITIES IN CONCURRENT CHEMORADIATION
Concurrent chemo radiation with cisplatin based chemotherapy, marked its success through a series of trials in improving not only the local control rate, but also the overall survival. In the late 1970s Soloway and colleagues demonstrated radio sensitization in a murine model of transitional cell carcinoma. In a study of 19 human cervical-cancer cell lines, Britten et al. found that radiotherapy and concomitant treatment with cisplatin increased the rates of death of these tumour cells. However, radio sensitivity was increased in only four cell lines, suggesting that the effect of this combined therapy is primarily caused by direct cytotoxicity .
Cisplatin is Cis-diamminedichloroplatinum, a water soluble coplanar complex, which is converted to its active form by replacement of its chloride ions with hydroxyl groups . The cytotoxicity of cisplatin is primarily ascribed to its interaction with nucleophilic N7-sites of purine bases in DNA to form both DNA–protein and DNA–DNA interstrand and intrastrand cross links . The basis for interaction between cisplatin and radiation may be appreciated at multiple levels, like
increased formation of toxic platinum intermediates in the presence of radiation- induced free radicals,
the capacity of cisplatin to scavenge free electrons formed by the interaction between radiation and DNA that may fixate otherwise reparable damage to DNA,
a radiation-induced increase in cellular cisplatin uptake,
a synergistic effect because of cell cycle disruption, and
The inhibition of repair of radiation-induced DNA lesions.
The toxicity of concurrent chemo radiation in carcinoma cervix can be attributed to 1) Cytotoxic effects of chemotherapy.
2) Toxicity due to pelvic radiation.
3) Enhanced toxicity due to synergistic effect.
Cytotoxic effects of chemotherapy:
Edward Chu in his “Cancer Chemotherapy Drug Manual” describes 13 toxicities due to cisplatin. The notable ones are nephrotoxicity, nausea & vomiting, myelosupression, neurotoxicity and ototoxicity. The other likely side effects are hypersensitivity, optic neuritis, papilloedema, cerebral blindness, transient elevation of liver function tests, metallic taste of food & loss of appetite, vascular events like myocardial infarction, cerebral infarction, Raynaud’s phenomena, azoospermia, alopecia and syndrome of inappropriate secretion of anti diuretic hormone.
Toxicity due to pelvic radiation:
Acute symptoms of the rectum can be seen early in the course of radiation therapy for cancers in the pelvic region. Symptoms usually begin following 20 Gy of standard fractionation. Early symptoms may include tenesmus, bleeding, and diarrhoea.
O’Brien et al. found that the presence of acute proctitis was the only factor to predict any of the late rectal symptoms of urgency, frequency, and diarrhoea . Similarly Acute sequelae during radiation commonly include frequency and dysuria. These symptoms typically occur following more than 20 Gy to the bladder with conventional fractionation.
Regarding treatment related lymph oedema there is a report of patients treated with surgery and radiation for cervical cancer. 41% had unilateral lymph oedema. Of these patients, 28% had a slight swelling, 6% had moderate swelling and 7% had severe swelling, which was interpreted as treatment-induced lymph oedema. 22% of the patients had lymph oedema that was severe enough to cause symptoms .
Most often we see patients after radical treatment of cervical cancer on follow up presenting with chronic pelvic pain, due to insufficiency fractures. Insufficiency fractures in the pelvic bones and femoral neck fractures do occur do to the effect of radiation on bone.
The bone marrow is one of the most radiosensitive organs in the pelvis. Approximately 40%
of the total body bone marrow reserve lies within the pelvic bone. Hematologic toxicity can be seen acutely during radiation and exposure to radiation can result in long-term myelotoxicity. The radiation dose, dose rate, and volume all affect the acute response of the bone marrow to therapy. When small bone marrow volumes are irradiated, bone marrow in unexposed areas of the body responds by increasing its population of progenitor cells meeting the demands for haematopoiesis. Therefore, acute effects are not seen unless a substantial portion of the marrow is exposed. With exposure to large bone marrow volumes, neutropenia occurs in 2–3 weeks followed by thrombocytopenia and then anaemia in 2–3 months.
Haematological toxicity due to pelvic radiation is very rare and do not lead to any life threatening events.
Enhanced toxicity in concurrent chemo radiation:
Similar to the enhanced tumour killing effect by combined chemo radiation, there is also increased incidence of toxicity in these patients. In the GOG 123 study by Keys et al, it is observed that the incidence of grade 3&4 toxicity between the radiation only arm and concurrent chemo radiation (with cisplatin) arm was comparable for genitourinary, cutaneous and neurological toxicity. But for haematological toxicity, the incidence was 21%
in the chemo radiation arm versus 1.6% in the radiation arm. Similarly for gastrointestinal toxicity, the incidence was 14.2% in the chemo radiation arm versus 4.8% in the radiation arm. These data clearly proves that there is enhance myelotoxicity, when cisplatin is combined with radiation. The myelotoxicity is more profound when radiation is combined with other chemotherapeutic agents other than cisplatin.
BONE MARROW AND CHEMORADIATION
Haematopoietic cells replicate and differentiate along lymphoid or myeloid lineages regulated by a network of hematopoietic growth factors and cellular interactions.
The hematopoietic system is also dependent on the microenvironment that consists of endothelial cells, adventitial cells, fibroblasts, macrophages, and fat cells. This microenvironment maintains hematopoietic function in part through the secretion of colony stimulating factors and in maintaining cell-cell contact.
Figure 2-Adapted from The blood supply of bone, London: Butterworths; 1971
The microenvironment is heterogeneous both in its function and anatomic structure. Haematopoiesis takes place in the extra vascular spaces between marrow sinuses, which are the channels through which blood flows in the bone marrow. These sinuses are the finer branches of a complex vascular network. The arterial blood supply of marrow comes predominantly from the nutrient artery that penetrates the cortex of bone, enters the marrow, and bifurcates into ascending and descending medullary arteries. These give rise to radial arteries that enter the canalicular system of cortex through the endosteum and become and endosteal capillaries can communicate. The cortical capillaries enter the marrow sinuses, which eventually collect and enter the central sinus from which blood leaves the marrow and enters the systemic venous circulation via emissary veins. The resulting interstitial spaces, which are composed of the various stromal cells, make up the hematopoietic microenvironment .
The geographical distribution of the bone marrow is relevant to understanding radiation effects. Although variations occur, the major functional sites are the pelvis and vertebrae that make up approximately 60% of the total body marrow. The ribs, sternum, skull, scapulae, and proximal portions of the femur and humerus also contain functioning marrow . In children, the humerus, femur, and other long bones are active, but marrow retraction from the peripheral (appendicular) toward central (axial) skeleton, and from diaphyseal to metaphseal in individual long bones gradually occurs, so that by age 20 years the mature adult distribution pattern is present.
Bone marrow dysfunction in the setting of therapy has several possible aetiologies ;
direct injury to hematopoietic stem cells or their depletion;
structural or functional damage to the stroma or microcirculation;
injury to other accessory cells that have regulatory (CSF secreting) functions;
perturbation of BM function by the underlying disease (e.g., leukemia); or
An inherent defect in BM stem cells associated with the underlying disease.
The bone marrow is sensitive to both the early and delayed effects of ionizing radiation. The hematopoietic syndrome constitutes a major complication after whole body exposures in the 2.5 to 10 Gy range. Death in this dose range is due primarily to the depletion of neutrophils and platelets. Although the marrow is sensitive to the effects of whole body exposure, local irradiation, even with relatively large fields such as those employed for total lymphoid irradiation, can be tolerated at fractionated doses of up to 20-40 Gy, with few if any apparent residual systemic effects. This discrepancy between the hematopoietic consequences of whole body versus local exposure presumably relates to the capacity of stem cells from the nonirradiated marrow and peripheral blood to seed the irradiated component.
Total dose (R) Time Morphological alterations
400 3 days Moderate decrement in
1000 8 days
Absence of precursor cells, dilated sinusoids, acute
2000 16 days
Marked decrement of all hematopoietic precursors,
5000 + 35 days
Nearly complete absence of hematopoietic precursors,
sinusoids less dilated
5000+ 3-12 months
Continued nearly complete hypoplasia; abortive recovery followed by progressive hypoplasia may
Table 3- Pathology of bone marrow after radiation
Figure 3-Adapted from Atlas of Radiation Histopathology, 1975.
Recovery of bone marrow after whole body exposure in the low- to midlethal range proceeds in an orderly fashion, with platelets and granulocytes achieving approximately normal values before erythrocytes do. As noted above, the importance of the marrow stroma and growth factors in supporting normal haematopoiesis has received considerable attention recently, and complete recovery of haematopoiesis after fractionated exposure may be limited, at least in part, by irreversible stromal injury, especially of the microvasculature, and/or by reduced production of growth factors.
The delayed consequences of localized exposure are less predictable than those of whole body irradiation. One key variable is age, with children exhibiting a greater capacity for morphologic restitution than adults. Complete recovery in adults is unusual at fractionated doses in excess of 50 Gy, possibly due to irreversible vascular-stromal injury.
Since the volume of irradiated marrow is relatively small, however, localized doses of this
magnitude have no discernible effect on overall haematopoiesis, as reflected by the number of formed elements in the peripheral blood.
Acute haematological toxicity is a common problem occurring in 20-25% of patients treated with pelvic radiation and cisplatin based chemotherapy. This can lead to hospitalization, treatment breaks, growth factors and antibiotics and rarely serious infections and mortality. Similarly haematological toxicity limits tolerance to treatment, and affects optimal chemotherapy delivery, which in turn associated with inferior clinical outcome. Both chemotherapy and radiation therapy are myelosuppressive. Radiation causes apoptosis of bone marrow stem cells and bone marrow stromal damage, resulting in myelosuppression.
Chemotherapy suppresses compensatory haematopoiesis in unirradiated bone marrow, leading to higher rates of hematologic toxicity than sequential chemotherapy and RT or either modality given alone.
Management of hematopoietic damage:
The management of patients with chronic bone marrow toxicity is currently suboptimal in that the available measures are supportive and rarely corrective. Erythrocyte transfusions, when haemoglobin is less than 10gm/dl. Platelet transfusions, when platelet count is below 20,000 cells per cu.mm. Granulocyte transfusions, in patients who are severely neutropenic (< 200/mm3) and have documented bacterial or fungal infections not responding to appropriate antibiotics, granulocyte transfusions are still a consideration.
Growth factor administration, singly or in combination, is now a common supportive measure in patients with red or white cell deficiencies. Erythropoietin, GM-CSF, G-CSF, IL-3, and M- CSF, growth factors that stimulate uncommitted progenitors (e.g., stem cell factor, IL-l, IL- 4, IL-6, IL- 11) are commonly used. Bone marrow transplantation used in patients with chronic marrow failure caused by hemopoietic stem cell depletion.
IMAGING OF ACTIVE BONE MARROW
The search for method to estimate the active bone marrow started in 1960’s, when a series of studies has been conducted at the Atomic Bomb Casualty Commission (ABCC) to determine gonadal and active bone marrow dose from medical radiography.
Figure 4- estimation of the active bone marrow
It was assumed that a human skeleton in a cubicle compartment split into many cubes which were labelled by transverse sections and by cube numbers within sections, as shown in the figure. Of the 476 compartments, 188 contained bone, and 288 did not. Sizes of medullary portions of bones were assessed by radiographs. They were then impregnated with beeswax by boiling, but incorporating contrast material (Pantopaque) in the beeswax to facilitate visualisation of the beeswax on radiography. Following solidification, all excess material was removed, and the bones were then cleansed with xylene and radiographed to assure complete filling. All bone sections were then re-weighed, marrow cavities evacuated in boiling xylene, and sections were removed at high temperature and dried. They were again
radiographed to assure complete removal of the mixture and initial weights were verified.
The resulting percentage distribution of bone marrow by compartments was tabulated .
Site Percentage of active marrow Cranium & mandible 13.1
Upper limb girdle 8.3
Cervical vertebrae 3.4
Thoracic vertebrae 14.1
Lumbar vertebrae 10.9
Lower limb girdle 26.1
Table 4- Active marrow percentage
Figure 5- Distribution of active bone marrow
The imaging methods used for active bone marrow estimation are bone marrow scintigraphy, Magnetic Resonance Imaging, Computed tomography and positron emission tomography.
Bone marrow scintigraphy:
Many radio tracers have been used for bone marrow scintigraphy. Fe-52 citrate is an ideal agent for assessing the physiological bone marrow activity. Lack of activity in spleen and liver helps to detect extramedullary haematopoiesis, but very expensive.
Technitium- 99m either as sulphur colloid or nanocolloid have identical marrow distribution pattern similar to Fe-52 citrate. But will not yield information regarding extramedullary haematopoiesis. Technitium-99m HMPAO is a marker for granulopoietic cells in the bone marrow. Technitium-99m labelled murine monoclonal antibody directed against non specific cross reacting antigen- 95 is also used as a granulopoietic marker.
When advanced diagnostic modalities like scintigraphy and magnetic resonance imaging were unavailable, CT scan was used to evaluate the bone marrow, but it is very non specific and does not represent the red active marrow. Hence its use for bone marrow imaging faded away. Recently Peter F. Caracappa at al implemented and evaluated methods for modeling the red bone marrow and for determining the radiation dose in a computational phantom derived from CT images .
Magnetic Resonance Imaging:
MRI is an extremely sensitive technique to detect bone marrow pathology.
Standard sequences for bone marrow pathology include T1-weighted spin-echo, short TI inversion recovery sequences (STIR) or T2-weighted fat saturated fast SE sequences. On T1- weighted MR images, marrow signal increases when the percentage of fat increases. It
decreases when the percentage of other cells increases. According to the region of the skeleton and to the part of the bone examined, haematopoietic marrow contains 25%–70%
cells with a longer T1 than fat. The greater the cellularity of the marrow, the lower the T1 MR signals intensity. In normal adults pattern the signal of fatty marrow in the peripheral skeleton is as intense as that of subcutaneous fat. The signal is less intense in the upper femoral metaphyses and in the pelvic bones, in which cellularity averages 50%. The signal of the vertebral bodies, which contain the richest marrow, is slightly lower than that of the pelvis .
Positron Emission Tomography:
Positron emission tomography has revolutionised the field of oncology and recently a DNA precursor 39-18F-fluoro-39-deoxy-L-thymidine (18F-FLT) has been developed. Uptake of this tracer is directly related to the rate of DNA synthesis. PET imaging is inherently more quantitative than SPECT imaging because of the ability to provide more accurate attenuation correction. It also help for the assessment of proliferation along a continuum of toxicity and response. Cells imaged with Tc-99m Sulfur Colloid may not reflect the status of hematopoietically active marrow particularly at low radiation doses. Tumour response can be evaluated simultaneously with the assessment of bone marrow toxicity, which is not available with radiocolloid imaging.
OBJECTIVES AND METHODOLOGY
1. Aim of the study.
2. Specific objectives.
3. Study design.
4. Data collection.
AIM OF THE STUDY
To systematically study the patients of carcinoma uterine cervix treated with concurrent chemo radiation and to arrive at a most viable therapeutic option with particular reference to sparing the pelvic bone marrow so that the option should be cost effective to be implicated in developing countries.
To study the carcinoma uterine cervix patients treated with concurrent chemo radiation. Also to explore the factors which actually predict the occurrence of haematological toxicity, mainly neutropenia in these patients.
To evaluate the dose volume histograms of these patients and to find the relation between the volumes of the pelvic bone (lower lumbar vertebra, sacrum, pelvis bone and upper end of both femora) irradiated with the occurrence of neutropenia.
To compare the different techniques of radiation to the pelvis and to explore the technique that will be effective in reducing the occurrence of neutropenia in patients treated with concurrent chemo radiation.
The radiation technique should be cost effective, as in our country there is less insurance coverage for the patients to support very sophisticated treatment options. It should be also less time consuming in high volume treating centres, where intensity modulated radiation therapy to every patients are difficult.
Patients diagnosed as carcinoma uterine cervix of International Federation of Gynecology and Obstetrics stage II- III, who were treated with radiation to the pelvis, with concurrent chemotherapy from July 2011 to September 2011 were included in the study. All basic investigations including renal, hepatic and cardiac assessment were done. Those patients with hemoglobin less than 10gm/dl received packed red blood cell transfusion.
Patients were planned for either conformal radiation therapy or rapid arc therapy. In 3D- conformal radiation therapy either four fields or five fields were used. Cisplatin is the chemotherapeutic agent which was used weekly up to 4-5 cycles along with radiation at a dose of 40 mg/m2. These patients were treated with 2-3 fractions of High dose rate brachytherapy and parametrial boost. And patients not fit for concurrent cisplatin based chemotherapy were excluded. 44 patients with the above criteria were included. All patients were counseled about the treatment.
A computed tomography without contrast, in the treatment position was obtained for all patients. 5mm cuts were used for 3D-conformal plan and 3mm cuts were used for rapid arc plan. The CT cuts were taken from the level of D12 vertebra to 5cm distal to the ischial tuberosities.
Patients were evaluated with renal, hepatic function tests every week, before every cycles of chemotherapy. Total WBC count was checked in all patients and in patients with counts less than 2000 cells per mm3, further chemotherapy was deferred. Patients with prolonged neutropenia or febrile neutropenia received growth factor support and antibiotics.
All patients underwent pelvic examination at 30 Gy and end of external radiation, to aid in planning of brachytherapy timing. All patients completed chemotherapy before undergoing brachytherapy.
Normal structures including the bladder, rectum and the bony pelvis were contoured. The bony pelvis included the lower lumbar vertebra, sacrum, ileum, ischium, pubis and upper end of the both femoral head. The external contour of the above bones was delineated as the bony pelvis. The PTV was delineated.
Figure 6- Normal tissue contouring- Bladder, rectum, pelvic bone
Figure 7- Bony pelvis delineated
34 DATA COLLECTION
In the study group 3 patients were planned for rapid arc, 25 patients with 4-field conformal technique and 16 patients with 5- field conformal technique. After planning dose volume histograms of all plans were generated.
Figure 8- 5-F CRT fields
Figure 9- DVH for 5-field conformal therapy
Figure 10- 4-F CRT fields
Figure 11- DVH for 4-Field Conformal therapy
Figure 12-Rapid arc plan
Figure 13- DVH for Rapid arc therapy
All patients were planned in the Eclipse 8.6, Varian Medical Systems, Palo Alto; CA. Anisotropic analytical algorithm was used. For 4-field conformal therapy, anterior, posterior and two lateral open fields were used. For 5-field conformal therapy one anterior and 2 pairs of lateral oblique fields with appropriate wedges are used. A margin of 5mm was allowed between the field edge and PTV to allow for the beam penumbra. Rapid arc plans (dual complementary arcs) with gantry angles 181-179 degree and 179-181 degree were done with the aim to achieve, organ at risk and healthy tissue sparing while enforcing highly conformal target coverage. The following constraints were applied
Organ at risk Dose constraints
Small bowel Less than 30% of volume to receive dose
more than or equal to 40Gy
Rectum Less than 30% of volume to receive dose
more than or equal to 40Gy
Bladder Less than 35% of volume to receive dose
more than or equal to 45Gy
Femoral head Less than 15% of volume to receive dose
more than or equal to 30Gy
Table 5- Normal tissue contraints applied for Rapidarc plan
All patients were planned for daily dose of 180cGy, for total dose of 5040 cGy in 28 fractions. Patients were aligned to the skin marks and a pair of orthogonal KV Xray images was obtained using the Varian On-board imager, and the treatment position was verified, everyday for Rapid arc and once a week for conformal therapy.
Other patients characteristics like age, stage of the disease, Hemoglobin before the start of treatment, height, weight, body mass index and the incidence of neutropenia in
these patients were analysed The WBC hematological toxicity was graded according to the RTOG acute morbidity scoring criteria from Grade 0 to Grade 3. There was no Grade 4 toxicity or any death due to low WBC counts in the study group.
RTOG grading WBC count
Grade 0 Counts more than or equal to 4000 cells/cu.mm
Grade 1 3000 to 4000 cells per cu.mm
Grade 2 2000 to 3000 cells per cu.mm
Grade 3 1000 to 2000 cells per cu.mm
Grade 4 Less than 1000 cells per cu.mm
Grade 5 Low counts causing death
Table 6- RTOG grading for WBC toxicity
Figure 14- The incidence of neutropenia comparing different techniques of radiation
4FCRT 5FCRT Rapid arc
• Toxicity in
• Toxicity in
RESULTS AND ANALYSIS Age distribution:
Out of the 44 patients, 8 patients were in the age group of 30-40 years, 17 patients were in the age group of 40-50 years, 18 patients were in the age group of 50-60 years and one patient aged more than 60 years.
Figure 15- Age distribution- Majority of them were in their 5th and 6th decade
Among the 44 patients, 7 patients belong to FIGO stage IIA1, 17 patients belong to stage II.A.2, 13 patients belong to II.B and 7 patients belong to III.
Figure 16- Stage II A2 and Stage II B constituted more than 50%
40 Neutropenia in the study population:
20 patients out of 44 patients did not develop neutropenia. 14 patients developed Grade 1 neutropenia, 7 patients developed Grade 2 neutropenia and 3 patients developed grade 3 neutropenia. Further chemotherapy was deferred in patients who developed Grade 2 and Grade 3 neutropenia.
Treatment technique versus neutropenia:
In the study group 3 patients were treated with rapid arc, 25 patients with 4- field conformal technique and 17 patients with 5- field conformal technique. The graph below depicts the incidence of the different grades of neutropenia, when different techniques are used.
Figure 17- Neutropenia noted more in 4FCRT compared with 5FCRT
0 2 4 6 8 10 12
4-field CRT 5-field CRT Rapid arc
41 Mean dose received by bony pelvis versus toxicity:
Using the Dose volume histogram the mean dose received by the bony pelvis for the given plan was calculated and related to low counts. It was observed than all patients whose mean dose were more than 3000 cGy developed toxicity, and only 22% of patients with mean dose less than 2500 cGy developed toxicity. This clearly state that mean dose volume is a predictor for low WBC counts.
<2500 cGy 2500-3000 cGy >3000 cGy
Grade 0 7 13 0
Grade 1 1 11 2
Grade 2 0 6 1
Grade 3 1 2 0
Toxicity % 22% 59% 100%
Table 7- Mean dose versus toxicity
42 Volume of the bony pelvis versus toxicity:
The total volume of the bony pelvis was measured in all patients and compared with the occurrence of neutropenia. It was observed than nearly 70% of all patients with bony pelvis volume less than 700 cm3 developed low WBC count, whereas 50% of patients with bony pelvis volume more than 700 cm3 developed low WBC count. This shows that when the volume of bony pelvis is less more proportion of the bony pelvis will receive low dose radiation, which in turn lead to neutropenia.
<700 cm3 700-800 cm3 800-900 cm3 > 900 cm3
Grade 0 2 8 5 5
Grade 1 2 6 4 2
Grade 2 2 1 2 2
Grade 3 1 1 0 1
Toxicity % 71% 50% 54% 50%
Table 8- Volume of bony pelvis versus toxicity
43 V 10 versus Toxicity:
V10 is defined as the volume of the organ at interest, which is receiving more than 10 Gy. In this study, there was higher incidence of low counts nearly 85%, when V10 was more than 90%. When V10 was less than 80%, the incidence of low counts was around 28%. So increase in the V10 volume also indicates increased incidence of low counts.
70-80% 80-90% >90%
Grade 0 5 14 1
Grade 1 1 10 3
Grade 2 0 5 2
Grade 3 1 1 1
Toxicity % 28% 53% 85%
Table 9- V10 versus toxicity
44 V 15 versus Toxicity:
V15 is defined as the volume of the organ at interest, which is receiving more than 15 Gy. In this study, when V15 was more than 80% nearly all patients developed low counts. When V15 was less than 70%, the incidence of low counts was around 42%. So increase in the V15 volume more than 80% also indicates increased incidence of low counts.
Grade 0 20 0
Grade 1 9 5
Grade 2 4 3
Grade 3 2 1
Toxicity % 42% 100%
Table 10- V15 versus toxicity
45 V20 versus Toxicity:
V20 is defined as the volume of the organ at interest, which is receiving more than 20 Gy. In this study, low counts were not observed in patients when V20 was less than 65%. The incidence of low counts was 15%, when V20 was between 65 to 70%. The incidence of low counts raised to 85% , when V20 was between 70 to 75%. All patients, who had V20 more than 75% developed low WBC counts.
<60% 60-65% 65-70% 70-75% 75-80% >80%
Grade 0 1 5 11 3 0 0
Grade 1 0 0 0 11 1 2
Grade 2 0 0 2 3 1 1
Grade 3 0 0 0 2 0 1
Toxicity % 0 0 15% 84% 100% 100%
Table 11- V20 versus toxicity
46 V30 versus Toxicity:
V30 is defined as the volume of the organ at interest, which is receiving more than 30 Gy. In this study, when V30 was less than 40%, 18% of the patients develop low WBC count. When V30 was more than 50%, the incidence of low counts was around 88%.
So increase in the V30 volume more than 50% also indicates increased incidence of low counts.
<40 40-50 >50
Grade 0 13 6 1
Grade 1 2 8 4
Grade 2 1 5 1
Grade 3 0 0 3
toxicity % 18% 68% 88%
Table 12- V30 versus toxicity
47 V40 versus Toxicity:
V40 is defined as the volume of the organ at interest, which is receiving more than 40 Gy. In this study, when V40 was more than 30% nearly all patients developed low counts. When V40 was less than 20%, the incidence of low counts was around 50%. But the relation between the bony pelvis volume and incidence of low WBC counts are less marked when we consider V40 or V50. Which implicate the importance of low dose volume, rather than high dose volume to predict the incidence of low WBC count.
<20 20-30 >30
Grade 0 13 7 0
Grade 1 7 4 3
Grade 2 3 4 0
Grade 3 3 0 0
Toxicity % 50% 53% 100%
Table 13- V40 versus toxicity
48 On multivariate analysis:
All these data were then subjected to multivariate analysis. Volume of pelvis irradiated, minimal dose, mean dose and the maximum dose received by the bony pelvis, volume of the bony pelvis, which received more than 5Gy, 10Gy, 15Gy, 20Gy, 30Gy, 40Gy and 50Gy were all included for the analysis. Of all variable V20 had a significant P value (0.03). Thus we can arrive that the volume of the bony pelvis which is receiving more than 20 Gy significantly relates to the hematological toxicity.
Standard Error P-value Lower 95% Upper 95%
Intercept 4.000545 0.046989 -16.3763 -0.11617
pelvis vol 0.000608 0.405303 -0.00175 0.000723
min dose 0.001735 0.279614 -0.00162 0.005434
max dose 0.000685 0.150736 -0.00038 0.002398
mean dose 0.001111 0.283011 -0.00347 0.001046
v5 0.048966 0.757519 -0.08427 0.114751
v10 0.054333 0.839767 -0.09935 0.121487
v15 0.060698 0.598444 -0.15562 0.091085
v30 0.013432 0.184969 -0.00912 0.04547
v40 0.004812 0.101226 -0.00167 0.017884
v50 0.029745 0.972787 -0.06147 0.059428
Table 14- Multivariate analysis: only V20 had significant P value
49 Comparison of various techniques – V20:
To compare the V20 of different techniques, all three plans (5-field conformal therapy, 4- field conformal therapy, Rapid arc therapy) were generated. The dose volume histograms of all these three plans were compared. DVH of 4-field CRT plans are very characteristic. They have a plateau of increased high dose volume, followed by a transition and decreased low dose volume. But as we observed that increased low dose volume is related to toxicity, there is high V20 in 4-field CRT. The V20 of 5-field CRT and rapid arc are low compared to 4- field CRT.
Figure 18- In the above example the V20 for 4-field CRT is around 80%, and the V20 for both rapid arc and 5-field CRT were about 70%
On analysis of the V20 of different treatment techniques, V20 of less than 70% was achievable in 28% of 4-field CRT plans, 56% of 5-field CRT plans and all patients with rapid arc technique. Rapid arc technique was planned with giving constraints for the bone. These data clearly states that with the help of 5-field CRT we can achieve decreased V20 volume, which in turn helps in reducing the incidence of low WBC counts.
Technique <70 % >70 % Percentage
4F (25) 7 18 28%
5F (16) 9 7 56%
RA(3) 3 0 100%
Table 15- V20 versus different treatment technique
Figure 19- V20 versus treatment technique
0 10 20
4-Field CRT 5-Field CRT Rapid arc
more than 70%
The primary goal of the study is to analyze the patients of carcinoma cervix who were treated with primary chemo radiation and to explore the possibilities of any predictor of hematological toxicity. Also to compare the different techniques, which are commonly used and to determine the technique which can significantly reduce the acute hematological toxicity . The treatment technique should not be laborious and also should be cost effective, primarily because the incidence of carcinoma cervix is more in developing countries like India.
In the eras of conventional planning, the efforts to reduce the bone marrow toxicity laid in shielding the femur head and the iliac wing. But with the advent of newer treatment techniques like intensity modulated radiation therapy many efforts were taken to reduce bone marrow toxicity with bone marrow sparing. Many studies were then on these lines to reduce the bone marrow toxicity. Brixey et al reported in a retrospective study the effect of intensity modulated radiation therapy in reducing the hematological toxicity, even when constraints for bone marrow were not applied . Similar observation was made in our study; all patients who were treated with rapid arc plans had decreased hematological toxicity, even when no constraints were applied. Following these efforts to implicate marrow sparing started when Lujan et al used iliac bone sparing and planned intensity modulated therapy and showed reduced hematological toxicity . But doubts rose whether iliac bone marrow sparing is alone enough to reduce bone marrow toxicity. The whole pelvis bone, which compromises 40% of the total body marrow, will be considered as a unnecessary constraint, which make optimization of the IMRT plans very difficult.
Bone marrow is widely divided into active red marrow and the inactive yellow marrow. The active red marrow is the main source of hematopoiesis. Imaging modalities to detect this active bone marrow were developed and these higher advances were incorporated into intensity modulated therapy, to spare the bone marrow. There was a paradigm shift from
“bone marrow sparing” to “active bone marrow sparing”.
Roeske et al used single photon emission computed tomography using sulfur colloid to delineate the active bone marrow and planned intensity modulated therapy. 
Figure 20- SPECT showing active bone marrow
The sulfur colloid is selectively taken up by the macrophages which are in the active bone marrow and then imaged. But SPECT had few problems. Quantitative assessment of active bone marrow was difficult and also sulfur colloid uptake reflected the active reticulo endothelial system rather than the active bone marrow.
PET CT imaging with [18F] FLT was a recent advance to delineate the active bone marrow. FLT is flurothymidine which is incorporated in the DNA during proliferation.
It is a very apt surrogate marker of the active bone marrow. FLT is more specific for early response and can be used as a early predictor of response .
Figure 21- F18 FLT PET showing active bone marrow
And recently Sarah M. McGuire et al proved that FLT PET scan based IMRT planning can be used for better IMRT planning without compromising planning target volume or the organ at risk . But FLT is very expensive with limited availability.
When on one side the works to delineate active bone marrow was going on, Brent S Rose et al developed the normal tissue complication probability for bone marrow toxicity in patients treated with carcinoma cervix. They concluded in their study,that ”Efforts to maintain V10 < 95% and V20 < 76% could significantly reduce haematological toxicity,