Evolution of Hypofractionated Radiotherapy in Breast Cancerkoustavmajumder1986
Hypofractionated radiotherapy in breast cancer is one of the major evolution. It started few decades back. We have to know its history and radiobiological perspective. In this presentation I have tried to cover as much as possible. It would be helpful for all Radiation Oncologist specially the trainees.
Evolution of Hypofractionated Radiotherapy in Breast Cancerkoustavmajumder1986
Hypofractionated radiotherapy in breast cancer is one of the major evolution. It started few decades back. We have to know its history and radiobiological perspective. In this presentation I have tried to cover as much as possible. It would be helpful for all Radiation Oncologist specially the trainees.
Hypofractionation in early breast cancer is no more a research scholars topic. Multiple studies with robust data have proven its utility. It may hold an important role in many countries with constrained resources. This is a short presentation incorporating important completed and ongoing trials. Feel free to use this.
The combined use of radiation therapy and chemotherapy in cancer treatment is a logical and reasonable approach that has already proven beneficial for several malignancies.
Hypofractionation in early breast cancer is no more a research scholars topic. Multiple studies with robust data have proven its utility. It may hold an important role in many countries with constrained resources. This is a short presentation incorporating important completed and ongoing trials. Feel free to use this.
The combined use of radiation therapy and chemotherapy in cancer treatment is a logical and reasonable approach that has already proven beneficial for several malignancies.
While the role of radiation therapy in carcinoma cervix management is undauntable for all stages. Recurrent carcinoma cervix need a lot of personalisation
Definition: Small cell lung carcinoma (SCLC) is a type of lung cancer that typically starts in the bronchi (large airways) and tends to grow and spread quickly. It accounts for approximately 10-15% of all lung cancers.
Characteristics: SCLC is characterized by small, oat-shaped cancer cells that rapidly divide and form large tumors. It is often associated with a history of smoking and has a strong correlation with tobacco exposure.
Aggressive nature: SCLC is considered highly aggressive, with a tendency to metastasize (spread) early to the lymph nodes and other distant parts of the body, such as the liver, bones, and brain. This rapid spread makes early detection and treatment crucial.
Limited and extensive stage: SCLC is classified into two stages: limited stage and extensive stage. Limited stage means the cancer is confined to one side of the chest and potentially adjacent lymph nodes, whereas extensive stage indicates that the cancer has spread beyond the chest to distant organs.
Treatment approach: The treatment of SCLC typically involves a combination of chemotherapy and radiation therapy. Surgery is generally not recommended for SCLC due to its aggressive nature and tendency to spread early. Chemotherapy, often in combination with immunotherapy, is the mainstay of treatment and can help shrink tumors and control the disease.
Prognosis: The prognosis for SCLC is generally poorer compared to non-small cell lung carcinoma (NSCLC) due to its more aggressive behavior and earlier metastasis. However, treatment advances and research efforts continue to improve outcomes for SCLC patients.
Supportive care: As with any cancer diagnosis, supportive care plays a critical role in managing SCLC. This includes addressing symptoms, managing pain, providing emotional support, and ensuring optimal quality of life for patients.
It's important to consult with healthcare professionals for an accurate diagnosis, personalized treatment plan, and ongoing monitoring for individuals suspected or diagnosed with small cell lung carcinoma.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
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Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
2. Rationale of Concurrent CT-RT
• Both Cisplatin and 5-FU are potent radiosensitizers.
• Concurrent use with RT seems to be synergistic.
• Failure rates with RT alone
• II B - 25-50%
• III – 50-75%
• Concept useful in other sites - H&N, lung, esophagus, bladder, anus
• Radiobiologically, CT-RT
• Inhibits the repair of SLDs from radiation
• Sensitizing cells to radiation
• Synchronizes cells to a particular radiosensitive phase of the cycle (G2 phase)
• Direct cytotoxicity
• Britten et al. * – CT+RT increase rates of deaths of tumour cells.
* Britten RA, Evans AJ, Allalunis-Turner MJ, Pearcey RG. Effect of cis- platin on the clinically relevant radiosensitivity of human cervical carcinoma cell lines.
Int J Radiat Oncol Biol Phys 1996;34:367-74
3. Indications
• As a definitive treatment in stage IB2 to IVA carcinoma cervix
• As a adjuvant treatment in post-radical hysterectomy in early stage
cases with high risk pathological features (positive lymph nodes,
positive parametria, positive margins).
4. Roadmap Concurrent chemo-radiotherapy in 1980s
Rose et al., Keys et al., Peters et al., Whitney et al., Morris et al. - 1999
NCI Clinical announcement- 1999
Pearcey et al. – NCI Canada
Green Meta-analysis, Lancet 2001
Lukka Meta-analysis, Clinical Oncol 2002
Green Meta-analysis update, Cochrane database systemic review-2005
Cochrane database systemic review update - 2010
5. Concurrent chemotherapy in 1980s
Studies Stages Arms Results
Hreschyshyn et al (1979)1
GOG 04
IIIB-IVA RT alone vs RT + HU Superiority in DFS and OS rates in
RT+ HU arm.
Significant toxicity (47%) in HU
arm.
Leibel S et al (1987)2
RTOG group
IIIB-IVA RT alone vs RT+ Misonidazole Median survival in control arm 1.9
yrs. vs 1.6 yrs. for Misonidazole
arm.
Stehman et al (1988)3
GOG 56 group
IIB-IVA RT + HU vs RT+ Misonidazole No difference in terms of PFS or
OS in two arms.
Although a trend favouring the HU
arm.
1. Hreschyshyn et al, Hydroxyurea or placebo combined with radiation to treat stages IIIB/IVA cervical cancer confined to pelvis. Int J Radiat Oncol Biol Physc, 1979;5:317.
2. Leibel et al. Radiotherapy with or without Misonidazole for patients with stage IIIB or IVA squamous cell carcinoma of uterine cervix. Prelimnary report of a Radiation Therapy Oncolgy
group randomised trial. Int J Radiat Oncol Biol Physc, 1987;13:541.
3. Stehman et al: randomised trial of hydroxyurea versus Misonidazole adjunct to radiation therapy in carcinoma cervix. A prelimnary report of a gynaecological oncology group study, Am J
Obstet Gynecol, 1988;159:87
6. • A series of five randomized trials in a variety of disease stages matured around then:
• Collectively, 1894 women were analysed and compared cisplatin based chemoRT to RT
alone (RTOG 9001, GOG 123, SWOG 87-97) and hydroxyurea (GOG 85 and 120). All
showed a significant reduction in the risk of recurrence and death with cisplatin-based
chemoRT.
GOG 85 [1] Whitney et al, JCO 1999
RTOG – 9001 [2] Morris M et al, NEJM 1999
GOG 120 [3] Rose PG et al, NEJM 1999
SWOG 8797/GOG 109 [4] Peters WA et al, Gynecol Oncol 1999
GOG 123 [5] Keys HM et al, NEJM 1999
1. Whitney CW, Sause W, Bundy BN, et al: Randomised comparison of fluorouracil plus cispla- tin versus hydroxyurea in stage IIB/IVA in carcinoma of the cervix. J Clin Oncol 17:1339-
1348, 1999
2. Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrent chemotherapy compared with plevic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340:1137-1143,
1999
3. Rose PG, Bundy BN, Watkins EB, et al: Con- current cisplatin-based radiotherapy and chemother- apy for locally advanced cervical cancer. N Engl J Med 340:1144-1153, 1999
4. Peters WA, Liu PY, Barrett RGW, et al: Cis- platin, 5-Fluorouracil plus radiation therapy are supe- rior to radiation therapy as adjunctive therapy in high risk, early stage carcinoma of the
cervix after radical hysterectomy and pelvic lymphadenectomy: Report of a Phase III inter group study. Presented at Soc Gynecol Oncol 30th Annual Meeting, San Fransisco, CA, February
5-9, 1999
5. Keys HM, Bundy BN, Stehman FB, et al: Cisplatin, radiation and adjuvant hysterectomy com- pared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N
Engl J Med 340:1154-1161, 1999
7. • Ca Cervix Stage IIB,III and IVA with negative para-aortic nodes
• 177 patients received cisplatin (50 mg/m2 IV) on days 1, 29, 5-FU (IV infusion, 1 g/m2 for 4 days) day2-
day5 and 30 to 33
• 191 patients received hydroxyurea (80 mg/kg orally twice weekly).
• Primary end points – PFS, OS
• Median Follow up – 8.7 yrs
Journal of Clinical Oncology, Vol 17, No 5 (May), 1999: pp 1339-1348
GOG 85, Whitney et al. (1999)
8. P = .033
With a median follow-up for survivors
of 8.7 years, the 5-year survival rate in
the cisplatin/5-FU arm was 60%,
compared with 47% for women in the
hydroxyurea arm.
CF HU P value
Percentage Progression 43% 53% 0.033
Percentage death 45% 57% 0.018
P = .018
9. Adverse effects
• predominately hematologic or gastrointestinal in both treatment groups.
• Severe life threatening Leukopenia was more common in the HU regimen (P , .00001).
[only six CF patients (4%) compared with 46 HU patients (24%)].
• Grade 3 or 4 gastrointestinal toxicity was slightly more common (not statistically significant)
for patients randomized to CF (8%) than for the HU group (4%).
• The late major complications rate (grade 3 and grade 4) was 16.2% at 3 yr for CF group and
16.5% at 3 yr for HU group.
GOG 85
Staged as IIB - receive 40.8-Gy/24 fraction EBRT to the whole pelvis, 40 Gy was to be delivered to
point A via one or two intracavitary applications (tandem and colpostats) of radium or its equivalent. If
necessary, a parametrial boost was given to bring them point-B dose to 55 Gy.
Staged as III or IVA - receive 51 Gy in 30 fractions, Point A received 30 Gy from one or two
Intracavitary implants. Point B received 60 Gy from both sources with or without a parametrial boost.
10. • Three-arm randomized trial, 526 pts
• stage II B (localized disease with parametrial involvement), stage III (extension of the tumor to the pelvic wall), or
stage IV A (involvement of the bladder or rectal mucosa).
• From April 1992 to April 1997.
(N Engl J Med 1999;340:1144-53.)
RT + Hydroxyurea RT+ weekly Cisplatin RT+Hydoxyurea+Cisplatin+5FuVs Vs
177 Pts. 176 Pts. 173 Pts.
GOG 120, Rose et al. (1999)
11. Staged as IIB - receive 40.8-Gy/24 fraction EBRT to the whole pelvis, 40 Gy was to be delivered to
point A via one or two intracavitary applications (tandem and colpostats) of radium or its equivalent. If
necessary, a parametrial boost was given to bring them point-B dose to 55 Gy.
Staged as III or IVA - receive 51 Gy in 30 fractions, Point A received 30 Gy from one or two
Intracavitary implants. Point B received 60 Gy from both sources with or without a parametrial boost.
12. GOG 120
RT+
HU
RT+Cis
platin
RT+HU/
Cis/5FU
P value
PFS 64% 67% 47% <0.001 (for both
Cisplatin arms)
No. of
deaths
89 59
(0.002)
57
(0.004)
• 526 pts
• Median FU – 35 mnths
• Primary end point – OS, PFS
• Patients who received the platinum-based
regimens had significantly longer progression-
free survival than those who received
hydroxyurea (P<0.001 for both comparisons)
13. • The highest combined frequency of grade 3 (moderate) and grade 4 (severe)
adverse effects was associated with treatment with radiotherapy and the three-drug
regimen (Frequency in the other two groups was similar. )
• Both grade 3 and grade 4 leukopenia in the group given radio-therapy combined
with treatment with cisplatin, fluorouracil, and hydroxyurea were more than
double the frequencies in the other two groups (P<0.001).
• Both grade 3 and grade 4 granulocytopenia in the group given radiotherapy
combined with cisplatin, fluorouracil, and hydroxyurea therapy were
approximately double those in the other two groups (P<0.001).
• Not mentioned delayed toxicity.
Adverse effects :
GOG 120
16. RTOG 9001, Morris et al. (1999)
(N Engl J Med 1999;340:1137-43.)
• Between 1990 and 1997, 403 women with
advanced cervical cancer
• Stages IIB through IVA or
• Stage IB or IIA with a tumor diameter of at least
5 cm or involvement of pelvic lymph nodes
• Primary end points – DFS, OS
• Median FU– 43 mnths
• RT Alone Arm ( receive 45 Gy of radiation to the pelvis
and para-aortic lymph nodes ) Or
• RT + CT Arm (45 Gy of radiation to the pelvis alone
plus two cycles of fluorouracil and cisplatin (days 1
through 5 and days 22 through 26 of radiation).
• Patients were then to receive 1 or 2 applications of low-
dose-rate ICRT (40 Gy to Point A), with a third cycle of
chemotherapy planned for the second intracavitary
procedure in the combined-therapy group.
17. Overall survival rates were significantly better among patients treated with radiotherapy and chemotherapy than among
those treated with radiotherapy alone (73 percent vs. 58 percent, P=0.004)
RTOG 9001
18. Disease-free survival at five years was 67 percent
in the combined-therapy group and 40 percent in
the radiotherapy group, according to Kaplan–Meier
analysis (P<0.001)
RTOG 9001
RT + CT RT P value
DFS 67% 40% <0.001
OS 73% 58% 0.004
19. • Acute moderate (grade 3) and severe (grade 4) side effects significantly more with combined
therapy than with radiotherapy alone
• No significant differences in the late effects between the treatment groups.
RTOG 9001
20. J Clin Oncol, 2004;22:872-880.
• Median FU – 6.6 yrs
• Patients with stage IB to IIB disease who received CTRT had better overall and disease-free
survival than those treated with EFRT (P-0.0001).
• Patients with more advanced stage disease IIIB-IVA, only PFS was improved (P-0.05), while
no statistical improvement in locoregional disease control or OS were noted.
• Late complications of treatment was similar for the two treatment arms
RTOG 9001 update, Eifel et al. (2004)
22. (N Engl J Med 1999;340:1154-61.)
• Women with bulky stage IB cervical cancers
(tumor, >4 cm in diameter).
• 369 women
• Primary end point – PFS, OS
• Median FU - 36 mnths
Radiotherapy alone or in combination with
cisplatin (40 mg per square meter of body-surface
area) once a week for up to six doses; maximal
weekly dose, 70 mg), followed in all patients by
adjuvant extrafascial hysterectomy.
GOG 123, Keys et al. (1999)
23. P < 0.001
The relative risks of progression of disease and death among the 183 women assigned to receive radiotherapy and
chemotherapy with cisplatin, as compared with the 186 women assigned to receive radiotherapy alone, were 0.51 (95
percent confidence interval, 0.34 to 0.75) and 0.54 (95 percent confidence interval, 0.34 to 0.86), respectively.
GOG 123
The disease recurred in 37% in RT alone arm and 21% in CT-RT arm.
24. The relative risk of death in the combined-therapy group as compared with the group given
radiotherapy alone was 0.54 (95 percent confidence interval, 0.34 to 0.86). (P=0.008).
The three year survival rates were 74 percent in the group given radiotherapy alone and 83 percent in
the combined- therapy group
GOG 123
P - 0.008
26. GOG 123 Update, Stehman et al. (2007)
Am J Obstet Gynecol. 2007 November ; 197(5): 503.e1–503.e6.
Three hundred seventy-four patients entered this trial. There were 369 evaluable patients;
186 were randomly allocated to receive RT alone
183 to receive CT+RT.
Radiation dosage was 45 Gy in 20 fractions followed by low dose-rate intracavitary application of 30 Gy to Point A.
Chemotherapy consisted of intravenous cisplatin 40 mg/m2 every week for up to six weekly cycles.
Total extrafascial hysterectomy followed the completion of RT by six to eight weeks.
Median FU – 101 mnths
27. 71% vs 60%
78% vs 64%
GOG 123 update
p< 0.004
p< 0.015
CT-RT RT alone P value
6-yr PFS 71% 60% <0.004
6-yr OS 78% 64% <0.015
28. • Late adverse events-
• At last follow-up there were 118 patients alive on the irradiation-only regimen and 135
patients alive on the combination regimen who could be assessed for long-term adverse
effects.
• Long-term adverse effects on the gastrointestinal tract, genitourinary tract, and skin were
uncommon in both regimens.
GOG 123 update
Conclusion : The concurrent administration of concurrent cisplatin
reduces the relative risk of recurrence and death by approx. 40%,
compared with patients of RT alone
29. Journal of Clinical Oncology, Vol 18, No 8 (April), 2000: pp 1606-1613
Patients with clinical stage IA2, IB, and IIA carcinoma of the
cervix,
Initially treated with radical hysterectomy and pelvic
lymphadenectomy, and who had positive pelvic lymph nodes
and/or positive margins and/or microscopic involvement of the
parametrium
• Patients were randomized to receive
• RT (116 pts) or RT + CT (127 pts.).
• Patients in each group received 49.3 Gy RT in 29
fractions to a standard pelvic field.
• Chemotherapy consisted of bolus cisplatin
70 mg/m2 and a 96-hour infusion of fluorouracil
1,000 mg/m2/d every 3 weeks for four cycles, with
the first and second cycles given concurrent to RT
SWOG 8797/GOG 109, Peters et al.,1999
30. SWOG 8797
CT-RT RT P value
4-yr PFS 80% 63% 0.003
4-yr OS 81% 71% 0.007
Primary end point – PFS
Secondary end point – OS
Median FU – 42 mnths
32. • Median FU – 62 mnths (5.2 yrs)
• 5 yr OS – 80% vs. 66% (p value - significant), in favour of CT-RT
• Benefit from the addition of CT was most evident among women with tumors larger than 2cm
(P=0.17, for size < 2 cm; P=0.009 for size > 2 cm)
SWOG 8797/GOG 109 update, Monk et al.,2005
33. Study Authors Year Arms Media
n FU
Patien
ts
RT details Stage Surgery OS Benifit PFS/DFS
Benifit
RTOG
9001
Morris 1999 RT(PA)
Vs
RT+CF
43
mnths
403 45 Gy/25# + PA
f/b
ICRT 40 Gy to point A
Bulky IB
+
IIB-IVA
N.A 73% vs
58%
(0.004)
67% vs
41%
(<0.001)
Eifel 2004 6.3
yrs
GOG
123
Keys 1999 RT
Vs
RT+C
36
mnths
369 45 Gy/25#
f/b
ICRT 30 Gy LDR to point A
Bulky
IB
Adjuvant
extrafasci
al
hysterecto
my
78% vs
64%
(0.015)
71% vs
60%
(0.004)
Stehman 2007 101
mnths
SWOG
8797
Peters 1999 RT
Vs
RT+CF
42
mnths
243 49.3 Gy/29# IA2,
IB,
IIA
Rad
Hysterect
omy+
Pelvic
LND
80% vs
66%
(0.003)
80% vs
63%
(0.007)
Monk 2004 62
mnths
GOG
120
Rose 1999 RT+HU
Vs
RT+C
Vs
RT+CFH
35
mnths
526 IB – 40.8/24# f/b 40 Gy
point A
IIB/IVA – 51Gy/30# f/b 30
Gy point A
IIB-IVA NA 10 yr OS-
53% vs
53% vs
34%
10 yr PFS
46% vs
43% vs
26%
Rose 2007 106
mnths
GOG
85
Whitney 1999 RT+CF
Vs
RT+HU
8.7 yrs 368 Same as GOG 120 IIB-IVA NA 5 yr OS
60% vs
47%
34.
35. Fallacies of Randomized CCRT trials
• No identical protocol in the randomized trials.
• Differences in inclusion criteria of the patients.
• No uniformity in Chemotherapy arm.
• No uniformity in RT arm
36. JCO February 15, 2002 vol. 20 no. 4 966-972
• Total 253 patients with stage IB to IVA squamous cell cervical cancer with central disease ≥ 5
cm or histologically confirmed pelvic lymph node involvement
• 127 pts. randomized to be treated with cisplatin (40 mg/m2 weekly) and RT, and
• 126 patients were treated with RT alone
• 50.4 Gy to the pelvis combined with brachytherapy.
Pearcey et al., NCIC, JCO 2002
37. • Median follow-up was 82 months.
CT-RT RT alone P value
PFS NA NA 0.33
3-yr OS 69% 66% 0.42
5-yr OS 62% 58%
38. Lancet 2001; 358: 781–86
• Systematic review of all known randomised controlled trials done between 1981 and 2000
• 17 published, two unpublished studies of chemoradiation for cervical cancer.
• 4580 randomised patients
• Cisplatin was the most common agent used.
Green Meta-analysis., Lancet 2001
39. Results for overall survival
The HR of 0·71 across all trials represents a 29% reduction in the risk of death or an absolute
improvement in survival of 12% (95% CI 8–16), from 40% to 52%.
40. PFS benefit
Benefit in Local recurrence and Distant metastasis
• Significant reduction in the rates of local recurrence (OR - 0.61, P – 0.00001) and
systemic recurrence (OR - 0.57, P - 0.00001)
42. Conclusions :
• Chemoradiation improves overall survival (hazard ratio 0·71, p<0·0001)
[whether platinum was used (0·70, p<0·0001) or not (0·81, p=0·20).]
• Greater beneficial effect was seen in trials that included a high proportion of stage I and II patients
(p=0·009).
• Absolute benefit
• PFS – 16%
• OS – 12%
• A significant benefit of chemoradiation on both
• Local (p<0·0001) and
• Distant recurrence (p<0·0001)
• Grade 3 or 4 haematological and gastrointestinal toxicities were significantly greater in the
concomitant chemoradiation group than the control group.
• There was insufficient data to establish whether late toxicity was increased in the concomitant
chemoradiation group.
43. Clinical Oncology (2002) 14: 203–212
Lukka Meta-analysis., 2002
• A systematic review of 8 randomized trials of cisplatin administered concurrently with external beam
radiotherapy versus radiotherapy without cisplatin for cervical cancer was combined with a meta-analysis of
results abstracted from published reports of the trials.
44.
45. Absolute reduction in the
risk of death of 11% (95%
CI, 7% to 15%).
• Six trials showed a trend in
improvement in local control
(except the Wong and Tseng
study)
• Distant metastatic rates
improved with Cisplatin based
chemo-RT
46.
47. The original review was based on nineteen trials (17 published and two unpublished) including 4580
patients.
This update includes twenty four trials (21 published, 3 unpublished) and 4921 patients, although due to
patient exclusion and differential reporting 61% to 75% were available for the analyses.
The Cochrane Library 2005, Issue 3
Patients with locally advanced cancer of the uterine cervix (FIGO stage IB-IVA).
Green Meta-analysis update, Cochrane 2005
48. • Two trials compared radiation plus hydroxyurea with cisplatin-based
chemoradiation alone (Whitney 1999) and cisplatin-based chemoradiation with or
without hydroxyurea (Rose 1999).
• One further trial of cisplatin-based chemoradiotherapy used different radiotherapy
on the control and treatment arms (Eifel 2004).
• Eight trials compared radiation alone with non-cisplatin based chemoradiation,
using 5-fluorouracil, mitomycin-C, bleomycin, epirubicin, Adriamycin and
cyclophosphamide, either as single agents or in combined regimens.
• Two of these trials gave further adjuvant chemotherapy in the chemoradiation arm
49. • The HR of 0.69 across all trials (95% CI = 0.61 to 0.77, P < 0.00001) represents a
31% reduction in the risk of death or an absolute improvement in survival of 10%
(95%CI = 7 to 13%) from 60% to 70%.
• Absolute improvement in progression-free survival of 13% (95% CI =10-16%) from
50% to 63%.
• Similar benefit with platinum vs non-platinum
• No suggestion that the scheduling of chemotherapy , the use of hydroxyurea in the
control arm or the frequency of chemotherapy, altered the effect of chemoradiation.
• Greater benefit for stage I-II.
• Significantly more serious GI and hematological toxicities
Conclusions :
50. Cochrane Database of Systematic Reviews 2010
18 RCTs (15 eligible)
N=3452
To assess the effect of chemoradiotherapy on all outcomes.
Cochrane Meta-analysis 2010
Individual Patient data (IPD) meta-analysis
51. Trend towards greater benefit of OS for early
stage disease:
10% improvement for IB-IIA,
7% for IIB,
3% for III-IV.
However, there was no significant
trend for the analysis of DFS by
stage (test for trend, P = 0.073)
52. • 5-yr OS improved by 6% (p<-0.001)
• Similar benefit for platinum (10 trials) vs non-platinum
• Greater benefit for adjuvant chemotherapy (2 trials, 19% OS benefit at 5 years)
• There were similar and significant absolute benefits of chemoradiotherapy on 5-year
locoregional DFS (8%, P < 0.001),
time to locoregional recurrence/ progression (6%, P = 0.00009) and
metastases-free survival (7%, P < 0.001).
53. Toxicity
• Trials that used HU on the control arm, a high level of serious haematological
toxicity was evident on both arms (slightly greater on the control arm, OR - 0.74,
95% CI- 0.53 to 1.03, P = 0.08)
• There was a significant increase in serious GI toxicity for the groups of trials
• Platinum-based chemoradiotherapy (P = 0.000002),
• Chemoradiotherapy plus additional chemotherapy (P = 0.001)
• Additional radiotherapy on the control arm (P = 0.000002).
• Data on late toxicity were not recorded for the majority of trials in the meta-analysis.
The available data suggest that only a small number of women across all trials (1% to
3%) experienced serious late toxicities, including nine deaths
54. Comparing the benefits of Meta-analysis
Benefit of CRT Green, 2001 Green, 2005 Cochrane, 2010
(IPD Meta-analysis)
No. of studies 19 total -
17 + 2(unpublished)
24 total –
21 + 3(unpublished)
13
Patients 4580 randomised
2865-3611 available
4921 randomised
3578 available
3452 randomised
3000 available
Absolute PFS Benefit 16% (47 to 63%) 13% (50 to 63%) 8% DFS Benefit
(50 to 58 %)
Absolute OS Benefit 12% (40 to 52%) 10% (60 to 70%) 6% (60 to 66%)
55. • Meta-analysis including
Cisplatin+RT vs RT alone
• Superior benefit in OS & PFS
with Cisplatin+RT
• Significantly enhanced toxicity
with Cisplatin + RT
(as in Cochrane 2010)
Meng et al., Onco targets and therapy, 2016
Forrest plot for OS
56. Toxicity of CT-RT
• 4580 pts – 19 RCTs
J.M. Kirwan et al., Radiotherapy and Oncology 68 (2003) 217–226
57. Grade 1 and 2 toxicities
• All grade 1 and 2 haematological toxicities were higher in the chemoradiation arms than the control.
• No significant increase in combined grade 1 and 2 toxicity for GIT, GUT, or dermatological toxicities
Grade 3 and 4 toxicities
• Significant differences were seen in grade 3 and 4 haematological and gastrointestinal toxicities
• Grd 3 or 4 GI Toxicity in 8% of patients in the CRT groups suffering severe or life threatening adverse
events
• No difference in grade 3 and grade 4 genitourinary (GUT) toxicity
58. Long term toxicity
• Long-term toxicity was only described in 8 trials, of which seven reported no
statistical difference in the incidence of long-term side effects
Conclusion :
• In view of the consistency and extent of the survival benefit for CRT the
additional acute toxicity appears to be acceptable.
59. • 7,336 patients – Pattern of care,
• 1,753 – Pattern of survival
• 12 institutions and were diagnosed between January 1, 2006, and December 31, 2008
• Primary end point - OS
• 5-year cumulative survival, 70.2% v 47.3% (CT-RT vs RT alone)
Nandkumar et al., POCSS, Journal of Global Oncology, 2015
60. • Optimal RT is defined as administering at least 45
Gy by external beam (minimum of 20 fractions)
plus intracavity brachytherapy (any dose)
• 5-year cumulative survival, 70.2% v 47.3% (CT-RT
vs RT alone)
63. • Closed prematurely
• There have been 121 deaths reported. There was a difference in OS at 4 years with 36% of patients dead of
disease on arm I compared with 45% of patients on arm II
• No difference in pelvic treatment failure between regimens, but there was an increase in the failure rate at
distant sites in the PVI FU arm.
65. Toxicities were more frequent in
arm A than in arm B (86.5% v
46.3%, respectively; P-0.001 )
Con Gem-Cis Con CTRT P value
3-yr PFS 74.4% 65% 0.029
OS 80% 69% 0.022
Toxixities 86.5% 46.3% 0.001
66. Way forward - New Combinations
• Carboplatin
• Paclitaxel + Carboplatin
• Gemcitabine
• Capecitabine
• Bevacizumab
• Cetuximab
• Ertotinib
• Celecoxib
No randomised phase III trial
• 5-year survival with this approach for LACC has reached a plateau of 50- 60%
and this also comes at the cost of high toxicities
• Protocols other than CCRT like induction chemotherapy or consolidative
chemotherapy have shown inconclusive advantage over CCRT alone and needs
further exploration in well-designed trials
GOG 04 PFE 68% VS 49%, OS 24 mon vs 13 mon.
Asecond GOG study (Protocol #56), reported by Stehman et al,14 compared HU to the hypoxic cell sensitizer, misonidazole. Patients with stage IIB to IVA disease and negative para-aortic lymph nodes were eligible. Again, the radiation therapy prescription was the same for both treatment arms. Grade 3 or 4 leukopenia occurred in 16.8% of patients receiving HU. Misonidazole was found to be inferior to HU. Pelvic control of tumor was better for patients receiving HU. This study validated the concept of chemoradiation for cervical carcinoma and maintained HU as the sensitizer of choice.With conclusion that Misonidazole was not superior to HU. The failure of HU to show a clear superiority over Misonidazole into the question the inherent benefit of hydroxyurea
After that series of randomised trials published in 1999.
After this, all patients underwent para-aortic lymphadenectomy via a retroperitoneal approach. Within 6 weeks of surgery, patients began radiation therapy with
standard fractionation. Patients whose tumors were staged as IIB were to receive 40.8-Gy external-beam therapy delivered homogeneously to the whole pelvis in 24 fractions. After completion of external-beam therapy, 40 Gy was to be delivered to point A via one or two intracavitary applications (tandem and colpostats) of radium or its
equivalent. If necessary, a parametrial boost was given to bring them point-B dose to 55 Gy. Those patients whose tumors were staged as III or IVA were to receive 51 Gy in 30 fractions if an intracavitary implant was not possible. Point A received 30 Gy from one or two Intracavitary implants. Point B received 60 Gy from both sources with or without a parametrial boost. Those patients treated solely with external-beam therapy were to receive 61.2 Gy. The total elapsed time for external and
intracavitary therapy could not exceed 10 weeks.
PFS was significantly different in favor of the 5-FU/CF regimen, with a risk reduction of 21%
43% pts in the CF group had disease progression whereas 53% in the HU group. 45 % pts have died in the CF arm compared with 57% in HU arm.
Most importantly, a 26% reduction in the risk of death
Whitney et al. (GOG 85; Ref 157) randomized 368 eligible patients to the receive either IV Cisplatin (50 mg/m2 infused at a rate of 1 mg/min with standard hydration on day 1 and 29) and 5-FU IV infusion (at a dose of 1,000 mg/m2/d on days 2-5 and 30-33), 4 hours before the first dose of external-beam radiotherapy (the CF regimen), or HU orally (at a dose of 80 mg/kg body weight every Monday and Thursday or Tuesday and Friday) each week of external-beam therapy. At median follow-up of 8.7 years, the difference in progression-free survival (PFS) and overall survival (OS) were statistically significant in favor of the CF group. The hazard ratio of progression/death of the CF group to the HU group was 0.79. Severe or life threatening leukopenia was more common in the HU group than in the CF group (24% vs 4%).
a randomized trial of radiotherapy in combination with three concurrent chemotherapy regimens — cisplatin alone; cisplatin, fluorouracil, and hydroxyurea; and hydroxyurea
alone —The duration of the radiotherapy was 10 weeks
The relative risk of progression of disease or death was 0.57 (95 percent confidence interval, 0.42 to 0.78) in the group given radiotherapy combined with cisplatin therapy and 0.55 (95 percent confidence interval, 0.40 to 0.75) in the group given radiotherapy combined with treatment with cisplatin, fluorouracil, and hydroxyurea, as compared with the group given radiotherapy combined with hydroxyurea therapy, after adjustment for the clinical stage of disease. Patients who received the platinum-based regimens had significantly longer progression-free survival than those who received hydroxyurea (P<0.001 for both comparisons)higher rates of survival and progressionfree survival among patients who were treated with radiotherapy and either cisplatin alone or cisplatin, fluorouracil, and hydroxyurea than among patients who were treated with radiotherapy and hydroxyurea alone. the relative risk of death was 0.61 (95 percent confidence interval, 0.44 to 0.85) in the group given radiotherapy combined with cisplatin therapy and 0.58 (95 percent confidence interval, 0.41 to 0.81) in the group given radiotherapy combined with treatment with cisplatin, fluorouracil, and hydroxyurea, as compared with the group given radiotherapy combined with hydroxyurea therapy
After completion of GOG 85, the group opened GOG 120447,448 for the same patient population, which was a three-arm randomized trial comparing irradiation plus hydroxyurea versus irradiation plus weekly cisplatin versus irradiation plus hydroxyurea, cisplatin, and 5-FU. Previously median follow-up was 35 months here it is 106 months. and incomplete pretreatment testing
(n 1), leaving 526 patients eligible for evaluation. Variations in
baseline patient and disease characteristicsamongtreatment regimens
were not statistically significant. The median follow-up for surviving
patients was 106 months with amaximumfollow-up of 153.2 months.
Local progression was significantly less among patients in the group given radiotherapy combined with cisplatin therapy (22%; P.014) and in the group given radiotherapy combined with cisplatin, fluorouracil, and hydroxyurea (21%; P.009) both PFS and OS was seen for stage IIB and III patient subgroups who received cisplatin-based chemoradation. While stage IIB and III subgroups have different survival rates, their hazard ratios are very similar.
compared the effect of radiotherapy to a pelvic and para-aortic field with that of pelvic radiation and concurrent chemotherapy with fluorouracil and cisplatin in women
with advanced cervical cancer.
The median duration of follow-up was 43 months. Estimated cumulative rates of survival at five years were 73 percent among patients treated with radiotherapy and chemotherapy and 58 percent among patients treated with radiotherapy alone (P=0.004). Cumulative rates of disease free survival at five years were 67 percent among patients in the combined-therapy group and 40 percent among patients in the radiotherapy group (P<0.001). The rates of both distant metastases (P<0.001) and
locoregional recurrences (P<0.001) were significantly higher among patients treated with radiotherapy alone. The seriousness of side effects was similar in the two groups, with a higher rate of reversible hematologic effects in the combined-therapy group.
IB to IIA of >5 cm, proven positive pelvic lymph nodes, or stage IIB to IVA carcinoma of the cervix in which patients were treated with either pelvic and para-aortic irradiation (best arm of RTOG Protocol 79-20) or pelvic irradiation and three cycles of concomitant chemotherapy with cisplatin (75 mg/m2) and 4-day infusion of 5-FU (1,000 mg/m2 per day).449 Results were updated by Eifel et al.397 With a median follow-up of 6.6 years for 228 survivors, the 8-year overall survival rate for women on the irradiation and cisplatin/5-FU arm was 67% versus 41% in the irradiation-only arm (p < .0001). Disease-free survival rates were 66% and 36%, respectively. There were no significant differences in late complications in the treatment groups.
the long-term follow-up of the RTOG 9001 trial demonstrated highly significant improvements in locoregional disease control, PFS, and OS for stage IB-IIB patients. However, for patients with more advanced stage disease IIIB-IVA, only PFS was improved (P.05), while no statistical improvement in locoregional disease control or OS were noted. Because only 26.7% of the patients in the RTOG trial had advanced stage disease (IIIB-IVA), this lack of improvement may be the result of the small sample size of advanced stage patients. Similarly, utilizing fluorouracil as a radiation sensitizer,
Gynecologic Oncology Group, we conducted a trial to determine whether weekly infusions of cisplatin during radiotherapy improve progression- free and overall survival among patients with bulky stage IB cervical cancer Women with evidence of lymphadenopathy on computed tomographic scanning or lymphangiography were ineligible unless histologic analysis showed that there was no lymph-node involvement. The cumulative dose of external pelvic and intracavitary radiation was 75 Gy to point A (cervical parametrium) and 55 Gy to point B (pelvic wall). Cisplatin was given during external radiotherapy, and adjuvant hysterectomy was performed three to six weeks later.
Median duration of follow up isonly 36 months. The disease recurred in 69 patients in the group given radiotherapy alone (37 percent) and 38 patients given radiotherapy and cisplatin (21 percent) (Table
4). This difference predominantly reflects the fact that there were fewer local recurrences in the combined- therapy groupThe relative risks of progression of disease and death among the 183 women assigned to receive radiotherapy and chemotherapy with cisplatin, as compared with the 186 women assigned to receive radiotherapy alone, were 0.51 (95 percent confidence interval, 0.34 to 0.75) and 0.54 (95 percent confidence interval, 0.34 to 0.86), respectively.
.
The rates of both progression-free survival (P<0.001) overall survival (P=0.008) were significantly higher in the combined-therapy group at four years
In the combined-therapy group there were higher frequencies of transient grade 3 (moderate) and grade 4 (severe) adverse hematologic effects (21 percent, vs. 2 percent in the radiotherapy group) and adverse gastrointestinal effects (14 percent vs. 5 percent).
Median duration of follow up is 101 months.
Higher % of the patients allocated to the CTRT had hysterectomy (96% vs 90%) and of those who did undergo hysterectomy there were more patients whose cervix had no residual cancer on microscopic examination (52% vs 41%). Probability of positive para-aortic nodes were sampled at the time of extra fasial hysterectomy was similar in both groups In an updated analysis with median follow-up of 101 months451 the 6-year progression-free survival rate for women treated with irradiation and cisplatin was 71%, compared with 60% for those treated with RT alone, after adjusting for age and tumor size (p < .004). The unadjusted 6-year overall survival rates were 78% and 64%, respectively (p < .015).
Southwest Oncology Group 8797 was a study for women with FIGO stage IA2, IB, or IIA carcinoma of the cervix with metastatic disease in the pelvic lymph nodes, positive parametrial involvement, or positive surgical margins at the time of primary radical hysterectomy with total pelvic lymphadenectomy. Patients had confirmed negative para-aortic lymph nodes; if the para-aortic lymph nodes were not sampled, the patients had confirmed negative common iliac lymph nodes. One hundred twenty-seven patients were randomized to treatment with pelvic EBRT with 5-FU infusion and cisplatin, and 116 were treated with irradiation alone.
The 3-year survival for women on the adjuvant cisplatin/5-FU and RT arm was 87%, compared with 77% for women on the pelvic irradiation arm.409 The difference was statistically significant. An updated analysis with 5.2-year median follow-up reported 5-year overall survival of 80% versus 66%, favouring postoperative chemoradiation in high-risk patientsProgression-free and overall survival are significantly improved in the patients receiving CT. The hazard ratios for progression-free survival and overall survival in the RT only arm versus the RT 1 CT arm are 2.01 (P 5 .003) and 1.96 (P 5 .007), respectively. The projected progression-free survivals at 4 years is 63% with RT and 80% with RT 1 CT. The projected overall survival rate at 4 years is 71% with RT and 81% with RT 1 CT. Grades 3 and 4 hematologic and gastrointestinal toxicity were more frequent in the RT 1 CT group.
Among the 122 patients assessable for toxicity in the CT 1 RT arm, there were 27 episodes of grade 4 toxicity in 21 patients (Table 6), most of which were hematologic. Among 112 patients randomized to RT alone and assessable for toxicity, four patients had grade 4 toxicity
The primary outcomes of our meta-analysis were overall and progression-free survival, and secondary outcomes were local and distant recurrence and acute and late toxicity. categorised by chemotherapy regimen (cisplatin vs non-cisplatin), scheduling (concomitant vs concomitant plus sequential), and frequency (platinum once per week vs a longer cycle time), and use of hydroxyurea in the control group (no hydroxyurea vs hydroxyurea).
HR for overall survival . HRs showed a highly significant benefit for overall survival with chemoradiation. The HR of 0·71 across all trials (table 2represents a 29% reduction in the risk of death or an absolute improvement in survival of 12% (95% CI 8–16), from 40% to 52%. Nevertheless, there was more evidence of a treatment effect in the trials that used platinum-based chemotherapy, than in the trials that used other drugs. Although the pooled HR estimate for the non-platinum trials was not significant, there was no evidence that the effect of chemoradiation in this group differed from that in the platinum group (p=0·48). Similarly, there was no suggestion that the scheduling of chemotherapy (p=0·36), the use of hydroxyurea in controls (p=0·41), or the frequency of chemotherapy (p=0·06) altered the effect of chemoradiation. Post-hoc analysis of the proportion of early-stage patients included in the trials (70% stage I and II vs <70% stage I and II) suggested that the effect of chemoradiation was greater in trials randomising a high proportion of stage I and II patients (p=0·009). Data from 13 trials were available to calculate HR for progression-free survival. Again, the overall results strongly favoured chemoradiotherapy, with an absolute improvement in progression-free survival of 13% (95% CI 13–19)—from 47% to 63%. However, the size of the effect seen in individual trials varied widely, with HRs from 0·38 to 1·36, which represented an absolutedetriment of 11% to an absolute benefit of 28% (p=0·001, table 3).
Acute toxicity was described in detail in only eight published trials,7–11,13,20,26 and one unpublished trial (Leborgne, table 1), Haematological toxicity was recorded most frequently (table 4), and was severe or life-threatening in more patients in the chemoradiotherapy group than in the control group (white cell count, 16% vs 8%; platelets, 1·5% vs 0·2%; haematological not otherwise specified, 29% vs 1%). Grade 3 or 4 gastrointestinal toxicity was also greater in the chemoradiotherapy group than in the control group (9% vs 4%), whereas neurological and dermatological toxicity did not differ significantly between groups, and genitourinary toxicity was slightly lower in the chemoradiotherapy group than in the control group (1% vs 2%)
Late toxicity was recorded systematically in only three studies,6,8,20 and was defined as toxicity beginning 42–90 days after completion of radiation. The main tissues
affected by late toxicity were the bladder and gastrointestinal tract, with no evidence of differences between the treatment groups. Systematic long-term follow-up was not available.
Studies investigating the use of concurrent cisplatin-based chemotherapy and radiotherapy have used various ‘standard’ treatments in the control arms. Hydroxyurea was administered to the control arm, in addition to radiotherapy, for two of the trials [5,6]; the others used radiotherapy without chemotherapy as the control treatment. In the RTOG 90-01 study, para-aortic lymph-node irradiation was added to pelvic irradiation in the control group
Subgroup analysis found that the relative risk for death was statistically significant in all six groups of trials described in the Methods section (Table 4). The relative risk of death was similar in studies using different control interventions (radiotherapy alone or radiotherapy plus hydroxyurea) and different experimental interventions (cisplatin alone or cisplatin plus 5FU).
Frequently haematological toxicity was noted in concurrent chemoradiotherapy arm. Four trials reported on late complications from treatment but none detected a significant increase in late toxicity when cisplatin-based chemotherapy was added to radiotherapy In two trials, there were no significant differences between radiotherapy plus cisplatin/fluorouracil and control in terms of late complications of treatment [1,6]. Rates of grade 3 or 4 late toxicity were 12% with cisplatin-based therapy versus 11% with radiotherapy alone in the trial by Morris et al. [1], and 16.2% with cisplatin-based therapy versus 16.5% with radiotherapy plus hydroxyurea in the trial by Whitney et al.
statistically significant effect in favour of cisplatin-based chemotherapy plus radiotherapy compared with radiotherapy without cisplatin (relative risk [RR] of death, 0.74; 95% confidence interval [CI], 0.64 to 0.86).
The pooled RR of death among the six trials that enrolled only women with locally advanced cervical cancer was 0.78 (95% CI, 0.67 to 0.90).
The pooled relative risk for the two trials in high-risk early-stage disease also demonstrated a statistically significant benefit for the addition of cisplatin-based chemotherapy to radiotherapy (RR=0.56; 95% CI, 0.41 to 0.77).
A 2005 update of a meta-analysis of concomitant chemotherapy and radiation therapy found 24 trials and concluded that chemoradiation improves overall survival and progression-free survival, whether or not cisplatin was used, with absolute benefits of 10% and 13% respectively.4 Acute side effects are generally of short duration and resolve withmedicalmanagement, while the late complications of radiotherapy lead to damage which can be difficult to reverse, and may permanently impair quality of
life. Details of late morbidity are more poorly documented, but with the exception of one trial (Leborgne 2000) where the regimen has now been modified, there is insufficient evidence to say whether it increased with combined therapy. Data on late toxicity have matured and more trials have become available. The highest
rate of grade 3 to 4 toxicity (58%) was in one trial of 33 patients treated with interarterial chemotherapy(Onishi 1999). The treatment arm in this trial had a late grade 3 to 4 toxicity rate of 89%. For the remaining 7 trials that reported serious late effects, the overall rates ranged from 1% to 19%. This probably reflects differences in the radiotherapy dose and scheduling between the
2 trials of CTRT FB ct shows 19% absolute benefit.
Dataonlate toxicity were not recorded for the majority of trials in the meta-analysis. Data on late rectal toxicity were available for seven trials, late bladder toxicity for five trials, and late intestinal and late vaginal toxicity for only four trials. Furthermore, within these trials there were substantial missing data. Therefore, there were insufficient data available to assess whether serious late toxicity is affected by the type of treatment. The available data suggest that only a small number of women across all trials (1% to 3%) experienced serious late toxicities, including nine deaths, but these data may not represent the true levels of late toxicity across all trials.
The study was closed prematurely when a planned interim futility analysis indicated that PVI FU/RT had a higher treatment failure rate (35% higher) and would, most likely, not result in an improvement in progression-free survival compared with weekly cisplatin/RT. The PVI FU/RT arm continues to show a higher risk of treatment failure (relative risk [RR] unadjusted, 1.29) and a higher mortality rate (RR unadjusted, 1.37). There was no difference in pelvic treatment failure between regimens, but there was an increase in the failure rate at distant sites in the PVI FU arm.
PFS at 3 years was significantly improved in arm A versus arm B (74.4% v 65.0%, respectively;P .029), as were overall PFS (log-rank P .0227; hazard ratio [HR], 0.68; 95% CI, 0.49 to 0.95),overall survival (log-rank P .0224; HR, 0.68; 95% CI, 0.49 to 0.95), and time to progressivedisease (log-rank P .0012; HR, 0.54; 95% CI, 0.37 to 0.79). Grade 3 and 4 toxicities were more frequent in arm A than in arm B (86.5% v 46.3%, respectively; P .001), including two deaths possibly related to treatment toxicity in arm A.