Pulmonary drug delivery system M.pharm -2nd sem P'ceutics
Cross trial
1. J O U R N A L
C L U B
Dr Ankita Singh
JR
RT & RM
IMS-BHU
1
2. N e o a d j u v a n t c h e m o r a d i o t h e r a p y p l u s
s u r g e r y v e r s u s
s u r g e r y a l o n e f o r o e s o p h a g e a l o r
j u n c t i o n a l c a n c e r ( C R O S S ) :
l o n g - t e r m r e s u l t s o f a r a n d o m i s e d
c o n t r o l l e d t r i a l
J o e l s h a p i r o , J j a n B v a n l a n s c h o t e t a l
L a n c e t o n c o l o g y , 2 0 1 5
2
3. Introduction
The incidence of esophageal adenocarcinoma is rapidly rising, whereas that of
squamous-cell carcinoma remains unchanged.
Despite adequate preoperative staging, 25% of patients treated with primary
surgery have microscopically positive resection margins (R1), and the 5-year
survival rate rarely exceeds 40%.
3
4. They reported a phase 2 trial of neoadjuvant chemoradiotherapy consisting of weekly
administration of carboplatin and paclitaxel with concurrent radiotherapy.
• with a low rate of serious toxic effects,
• a complete resection with no tumor within 1 mm of the resection margins (R0) was
achieved in all patients who underwent resection
4
7. S t u d y d e s i g n
Multicenter, randomized phase III, prospective, clinical trial.
The trial enrolled 368 patients
Between March 30, 2004, and Dec 2, 2008, from eight Dutch participating
centres
Initial results were published in 2012 after a minimum follow-up of 24 months
(median follow-up 45 months).
Update reported the long-term results after a minimum follow-up of 5 years in
2015.
7
8. Chemoradiotherapy for Oesophageal cancer followed
by Surgery Study (CROSS)
Randomized
Neoadjuvant
chemoradiotherap
y plus Surgery
Surgery Alone
8
9. Pa t i e nt Se l e ct i on cr i t er i a
-
Inclusion criteria
• Histologically proven squamous cell carcinoma, adenocarcinoma or undifferentiated carcinoma
of the intrathoracic esophagus.
• Surgical resectable (T2-3, N0-1, M0), as determined by Endoscopic Ultra Sound (EUS).
• T1N1 tumors are eligible ( T1N0 tumors and in situ carcinoma are not eligible)
• Tumor length longitudinal ≤ 8 cm and radial ≤ 5 cm.
• If tumor extends below the gastroesophageal (GE) junction into the proximal stomach, the
Bulk of the tumor must involve the esophagus or GE junction.
Tumor must not extend more than 2 cm into the stomach.
Gastric cancers with minor involvement of the GE junction or distal esophagus are not eligible
9
10. • No invasion of the tracheobronchial tree or presence of tracheoesophageal fistula
• Non pregnant, non-lactating female patients.
• Sexually active patients of childbearing potential must implement effective contraceptive
practices during the study when treated with chemotherapy.
• Age ≥ 18 and ≤ 75
• ECOG performance status 0, 1, or 2
• Adequate hematological, renal, hepatic and pulmonary functions defined as:
granulocytes ≥ 1.5 x 109/L
platelets ≥ 100 x 109/L
total bilirubin ≤ 1.5 x upper normal limit
creatinine ≤ 120 μmol/L
FEV1 ≥ 1.5 L
10
11. • Written, voluntary informed consent
• Patients must be accessible to follow up and management in the treatment center.
11
12. Exclusion criteria
• Past or current history of malignancy other than entry diagnosis except for non-
melanomatous skin cancer, or curatively treated carcinoma in situ of the cervix or a “cured”
malignancy more than five years prior to enrollment
• Previous chemotherapy and radiotherapy.
• New York Heart Association Class III/IV and no history of active angina.
Documented myocardial infarction within the 6 months preceding registration
(pretreatment ECG evidence of infarct only will not exclude patients).
Patients with a history of significant ventricular arrhythmia requiring medication or congestive
heart failure.
History of 2nd or 3rd degree heart blocks
12
13. • Pre-existing motor or sensory neurotoxicity greater than WHO grade 1
• Active infection or other serious underlying medical condition which would impair the ability of
the patient to receive the planned treatment, including prior allergic reactions to drugs
containing Cremophor, such as teniposide or cyclosporin.
• Dementia or altered mental status that would prohibit the understanding and giving of informed
consent
• Inadequate caloric- and/or fluid intake
• Weight loss > 10%
13
14. Randomisation
Patients were randomly assigned 1:1 to each treatment group, and were stratified
according to
• Histological tumour type (adenocarcinoma vs squamous cell carcinoma),
• Treatment centre,
• Clinical nodal status (cN0 vs cN1), and
• WHO performance score
14
16. Pre-treatment staging
• History taking;
• Physical examination;
• Pulmonary-function tests,
• Routine hematologic and biochemical tests;
• Upper gastrointestinal endoscopy with histologic biopsy and endoscopic Ultrasonography;
• Computed tomography of the neck, chest, and upper abdomen;
• External ultrasonography of the neck, with fine-needle aspiration of lymph nodes when cancer
was suspected.
16
17. Treatment
1 . N e o a d j u v a n t t r e a t m e n t
The total duration of neoadjuvant treatment was 23 days.
(5 days per week in weeks 1, 2, 3, and 4, then 3 days in week 5).
17
18. Chemotherapy regimen
• Paclitaxel 50 mg/m2 and Carboplatin AUC = 2 will be given by intravenous infusion on days 1,
8,15, 22 and 29.
• All patients were intravenously premedicated with dexamethasone, clemastine,
and ranitidine as well as standard antiemetic agents.
• The patients were closely monitored for toxic effects of chemotherapy
18
19. R a d i o t h e r a p y
Fractionation schedule
• A total dose of 41.4 Gy will be given in 23 fractions of 1.8 Gy, 5 fractions per week,
• With concurrent chemotherapy starting the day 1 of the first cycle of chemotherapy.
• 3-D conformal radiation technique
Position of the patient
• The patient will be positioned in supine position.
• Reproducibility will be assessed by orthogonal laser beams
Simulation
Planning CT scan from the cricoid to L1 vertebra with a slice thickness of 5 mm, with the patient in
treatment position.
19
20. GTV
• Primary tumor and any enlarged regional lymph nodes, drawn on each CT slice.
• GTV was determined using all available information
(physical examination, endoscopy, EUS, CT-thorax/abdomen)
PTV
• A proximal and distal margin of 4 cm,
• In case of tumor extension into the stomach, a distal margin of 3 cm will be chosen.
• A 1.5 cm radial margin around the GTV provided to include the area of subclinical involvement
around the GTV and to compensate for tumor motion and set-up variations
OAR
Lungs, Heart, Spinal Canal
Definition of Target volumes
20
21. V A R I A T I O N S O F N A C T - R T
Chemoradiotherapy delayed by 1 week until
recovery:
1. If on days 8, 15, 22, or 29
• WBC count was lower than 1·0 × 109cells/L
• Platelet count was lower than 50 × 109cells/ L,
2. In case of mucositis with oral ulcers or
protracted vomiting despite antiemetic
premedication.
Chemotherapy withheld:
• Febrile neutropenia,
• Persistent creatinine clearance of less than
50% of the pretreatment level,
• Symptomatic cardiac arrhythmia or AV block
(with the exception of first-degree AV block),
• Other major organ toxicity at grade 3 or
worse (with the exception of oesophagitis)
21
22. S u r g e r y
Patients in the chemoradiotherapy–surgery group underwent surgery as soon as possible after
completion of chemoradiotherapy (preferably, within 4 to 6 weeks)
Patients in the surgery group were treated as soon as possible after randomization.
Tumors
• extending proximally to the tracheal bifurcation –
transthoracic approach with 2 -field lymph-node dissection
trans hiatal approach
• involving the esophagogastric junction- a trans hiatal resection was preferred.
• Peri truncal dissection was carried out with both approaches.
22
23. For all other tumors, the approach depended on the characteristics of the
patient and on local preferences.
Gastric-tube reconstruction with a cervical anastomosis was the preferred
technique for restoring the continuity of the digestive tract.
23
24. P a t h o l o g i c a l a n a l y s i s
The resection specimen was evaluated using the standard protocol
• Margins,
• Tumor type and extension,
• Lymph nodes.
In the absence of macroscopic tumor, any abnormal-appearing tissue was paraffin-
embedded in total in order to make an adequate assessment for the presence of residual
tumor and the effects of therapy.
24
25. The response to therapy graded & classified as per the degree of histo morphologic
regression:
Grade 1- No evidence of vital residual tumor cells (pathological complete response);
Grade 2- Less than 10;
Grade 3- 10 to 50%;
Grade 4- more than 50%.
If a vital tumor was present at 1 mm or less from the proximal, distal, or
circumferential resection margin, it was considered to be microscopically positive
(R1).
vital residual tumour cells
25
26. F o l l o w u p
After treatment completion,
• 1st year : every 3 months.
• 2nd year: every 6 months,
• Annually thereafter until 5 years after treatment.
Additional interim visits were scheduled if complaints such as renewed dysphagia
and unexplained weight loss or pain arose before the next scheduled visit.
Diagnostic investigations only undertaken as necessary during follow-up.
No data for adverse events were collected beyond the initial report of this trial.
26
27. O u t c o m e s
• Primary end point:
Overall Survival
• Secondary end points:
Progression free Survival
Progression free interval
27
28. Progression-free survival
• Interval between randomisation and the earliest occurrence of disease progression
resulting in primary (or per operative) irresectability of disease, locoregional
recurrence (after completion of therapy), distant dissemination (during or after
completion of treatment), or death from any cause.
This definition for progression free survival was taken from the modified STEEP criteria
for neoadjuvant treatment trials
Progression-free interval was similar to progression-free survival, with the difference
that treatment-related deaths and non-oesophageal cancer-related deaths were not
counted as events.
28
29. S t a t i s t i c a l a n a l y s i s
An intention-to-treat principle.
To detect a difference of 6 months in median overall survival
(22 months in the neoadjuvant chemoradiotherapy plus surgery group vs 16 months
in the surgery alone group),
according to a two-sided test they calculated that at least 175 patients were needed
in each treatment group.
The statistical significance level was set to 0·05.
Kaplan-Meir: OS &PFS
Log Rank Test: to ascertain significance
29
34. R e s u l t s : i n i t i a l a n a l y s i s
• For surviving patients, the median follow-up was 45.4 months.
• The median disease-free survival for patients who underwent resection was not reached
in the chemoradiotherapy– surgery group and was 24.2 months in the surgery group
(P<0.001).
• An intention-to-treat analysis that included all patients showed a median overall survival
of 49.4 months in the chemoradiotherapy–surgery group versus 24.0 months in the
surgery group(P = 0.003).
• The observed survival in both groups was superior to the anticipated survival and to that
reported in earlier randomized trials
34
35. P a t h o l o g i c a l a s s e s s m e n t
Neoadjuvant chemoradiotherapy
plus Surgery
(n= 161)
Surgery Alone
(n=161)
148( 92%) 111(69%)
Ro resection
Neoadjuvant
chemoradiotherapy plus
Surgery
SCC AdenoCarcinoma
47 (29%) 18/37
(49%)
28/121 (23%)
P=0.008
P <0.001
Pathological complete response (ypT0N0)
35
36. A median of 15 lymph nodes were resected in patients in the chemoradiotherapy–
surgery group, as compared with 18 in patients in the surgery group (P = 0.77).
One or more positive lymph nodes in the resection specimen were found in 50 patients
(31%) in the chemoradiotherapy–surgery group, as compared with 120 patients (75%)
in the surgery group (P<0.001)
36
37. Adverse events during
neoadjuvant chemotherapy &
after surgery
Adverse events were graded according to the National Cancer Institute’s Common Terminology
Criteria for Adverse Events, version 3.0.10
37
40. Haematological toxicity
( >/= Grade 3)
Non- Haematological toxicity
(>/= Grade 3)
13(8%) 18( 11%)
Most common
Leukopenia
11(16%)
Anorexia
9(5%)
Fatigue
5(3%)
Of 171 patients who received any neoadjuvant chemoradiotherapy
162 (95%) were able to complete the entire neoadjuvant chemoradiotherapy
regimen.
164 (92%) received the full dose of radiotherapy.
2 patients (1%) received a higher dose of radiotherapy (45.0 and 54.0 Gy,).
The most common reason for not completing all chemotherapy cycles was a low platelet count.
40
41. Neoadjuvant
chemoradiotherapy
plus Surgery
(n= 180)
Surgery Alone
(n= 188)
Underwent Surgery 168(94%) 186(99%)
• Consent Withdrawn 2 -
• Patient’s decision 2 1
• Disease Progression 7 1
• Diagnosis of 2nd Cancer
before Surgery
- 1
• Death before Sx
( due to toxic effects of
CT-RT )
1 -
41
42. Neoadjuvant
chemoradiotherapy
plus Surgery
(N= 178)
Surgery Alone
( N = 188)
Resection 161 ( 90%) 162 (86%)
• Trans hiatal
resection
72(45%) 72 (44%)
In 7 of 168 patients (4%) in the chemoradiotherapy–surgery group, a resection
was not possible because the primary tumor or lymph nodes were identified during
surgery
as unresectable, as compared with 25 of 186 patients (13%) in the surgery group
(P = 0.002).
The median time between randomization and surgery was 97 days in the chemo
radiotherapy– surgery group and 24 days in the surgery group.
The median time between the end of chemoradiotherapy and surgery was 6.6
weeks .
42
43. Median Overall survival
NA CT-RT group : 48.6 months
Surgery alone group: 24.0
months
The Final day of follow up
was
Dec 31, 2013.
Minimum FU- 60 months
Median FU – 84.5 monhs
( At the time of analysis)
43
44. NA CT-RT group Surgery alone
group
SCC 81.6 months 21.1 months
AC 43.2 months 27.1 months
Median Overall Survival as per
tumour type
44
46. During follow-up, 16 patients died from treatment-related causes (i.e, during neoadjuvant
chemoradiotherapy or during postoperative hospital stay)
• neoadjuvant chemoradiotherapy plus surgery group: 9
• surgery alone group : 7
23 patients died from non-disease-related causes beyond the first 90 days postoperatively
• neoadjuvant chemoradiotherapy plus surgery group : 13
• surgery alone group: 10
46
48. • The estimated number of patients who need to be treated to prevent one additional death
at 5 years was 7·1
• The overall survival benefit of neo adjuvant chemoradiotherapy plus surgery was
generally confirmed across subgroups.
• Although univariable and multivariable hazard ratios for individual subgroups were
reported for informative purposes, no significant interactions in treatment effect were
identified for any of the subgroups, which means that differences in treatment effect
between subgroups could well have arisen by chance, and the overall treatment
effect should be regarded as valid for all considered subgroups.
48
50. NA CT RT
+ Sx group
Sx Alone
Group
SCC 74.7
months
11.6
months
ACA 29.9
months
17.7
months
50
51. Neoadjuvant
chemoradiotherapy
plus Surgery
Surgery Alone
1 year 71 % 54%
2 year 60 % 41%
3 year 51 % 35%
5 year 44 % 27%
Progression free survival At the end of:
• The estimated number of patients who need to be treated to prevent one
additional disease progression at 5 years was 6·1
• The progression-free survival benefit of neoadjuvant chemoradiotherapy plus
surgery was generally confirmed across subgroups
51
53. Disease progression during treatment (causing adjustment from curative to
palliative treatment intent) occurred in 17 patients in the neoadjuvant chemo radio
therapy plus surgery group and in 26 patients in the surgery alone group.
The reduction in locoregional & distant progression and distant progression was
already apparent during the first 6 months of follow-up and remained significant
after the first 24 months of follow up.
Indicating that the effect of reduction in locoregional progression continued for an
extended period after randomization.
Suggesting that the reduction in distant progression mainly occurred within the first
24 months after randomization.
53
55. These long-term results, after a median follow-up for surviving patients of 84
months, confirm the initially reported survival benefit for neoadjuvant chemo
radiotherapy plus surgery compared with surgery alone.
The improvement in distant disease control occurred within the first 2 years after
initiation of treatment, whereas the improvement in locoregional control
continued for a longer period.
These findings further support the clinical value of this multimodality treatment
strategy.
55
56. The overall survival benefit and the progression-free survival benefit were
confirmed for both histological subtypes of oesophagal or oesophagogastric
junctional Cancer.
No clear evidence exists to support the assumption that the adjusted overall
treatment effect of neoadjuvant chemoradiotherapy does not also apply to patients
with adenocarcinoma.
They therefore conclude that both patients with squamous cell carcinoma and
those with adenocarcinoma benefit significantly from the CROSS multimodality
treatment regimen
56
57. In the CROSS trial, not only locoregional control, but also distant disease control
improved significantly in the neoadjuvant chemoradiotherapy plus surgery group.
• If fewer locoregional recurrences occur, then possibly less distant dissemination
develops from these locoregional recurrences
• Effective treatment of the primary tumor in the presence of disseminated disease has
been reported to prolong survival in some cancer types
• Improved distant disease control could be caused by a direct systemic effect of
chemotherapy.
57
58. They reported a significant reduction in distant disease progression already within the first
6 months after randomisation .
Such an early reduction in distant disease progression, without evidence of a reduction
beyond the first 24 months, supports a direct systemic effect of this neoadjuvant
chemotherapy regimen.
58
59. Results from this trial might not be readily extrapolated to
• Patients with poorer performance status,
• Older patients, or
• Those with tumours located in the proximal or middle oesophagus,
• Because of the relative scarcity of patients in these categories.
The value of this treatment regimen will need to be confirmed for these patients in future
follow-up studies.
59
60. C o n c l u s i o n
Chemoradiotherapy according to the CROSS regimen improves long-term overall and
progression-free survival in patients with oesophageal and junctional cancer.
This improvement is statistically significant and clinically relevant for both squamous
cell
carcinoma and adenocarcinoma subtypes.
Neoadjuvant chemoradiotherapy according to CROSS followed by surgical resection
should be viewed as a standard of care for patients with resectable locally advanced
oesophageal or junctional cancer.
60
