Jaw and other orofacial pain in patients receiving vincristine for the treatment of cancer Gillian M. McCarthy, BDS, MSc,” and Jamey R. Skillings, London, Ontario, Canada THE UNIVERSITY
OF WESTERN
BSc, MD, FRCPC, MSC,~
ONTARIO
This prospective cohort study investigated orofacial pain occurring as a manifestation of vincristine neurotoxicity. Forty cancer patients (28 to 63 years of age) receiving vincristine were given baseline interviews and orofacial examinations, which were repeated weekly for 7 weeks of treatment. Twenty-two patients (55%) had neurotoxicity manifesting as orofacial pain. Onset was usually 3 days after vincristine administration; mean duration was 2 days. Twenty patients (50%) were affected in the first week: nine (22%) with severe and five (12%) with moderate pain. Symptoms were mild and infrequent in subsequent weeks. Eighteen control patients receiving chemotherapy without vincristine had no comparable orofacial symptoms. Multiple sites in the distribution of the trigeminal and glossopharyngeal nerves were affected: primarily the temporomandibular joint, mandible, throat, ears, and mandibular teeth. The frequency of orofacial pain increased with younger age. Pain was significantly associated with smaller body surface area (p < 0.05) indicating a dose-related toxicity, and with sociodemographic variables including smoking (p < 0.05). (ORAL SURC ORAL MED ORAL PATHOL 1992;74:299-304)
T
here has been an increasing number of reports of acute vincristine neurotoxicity that include effects on the trigeminal nerve.l-4 Jaw pain, which can be very severe,has been the most consistently reported manifestation. It can occur within hours of the administration of vincristine and can resolve spontaneously within days.‘, S* Transient dental pain9 and throat pain59lo have also been reported. The head and neck manifestations of neurotoxicity resulting from cancer chemotherapeutic agents have been reviewed, and the frequencies of symptoms of vincristine neurotoxicity other than pain have been presented elsewhere.” Kaplan and Wiernik6 reviewed the neurotoxicity of antitumor agents. Chemotherapeutic agents other than vincristine cause neurotoxicity, but the use of these agents has not been associated with orofacial pain, although severejaw pain has been noted after the administration of vinblastine. aAssistant Professor, Division of Oral Biology, Faculty of Dentistry. bAssociate Professor, Department of Oncology, and London Regional Cancer Centre. 7/13/34109
The specific objectives of this study were (1) to measure the frequency of orofacial pain occurring as a manifestation of neurotoxicity in patients receiving cancer chemotherapy with vincristine and (2) to identify factors associatedwith orofacial pain occurring as a manifestation of neurotoxicity in patients receiving cancer chemotherapy with vincristine. METHODS
Consecutive cancer patients who were scheduled to start combination chemotherapy were eligible for inclusion in the study. Exclusion criteria were previous chemotherapy, radiotherapy to the head and neck, age of more than 70 years, minors, inadequate renal function (serum creatinine >140 pmol/L), white blood cell count 35 pmol/L), mental incompetence or psychiatric disorders, and no informed consent. Vincristine
group
Forty patients, with a mean age of 45 years (range 28 to 63 years) were enrolled. This study population has been previously described.” The drug combina299
300
McCarthy
and Skillings
OKU
Sum7 ORAL MOD ORAL
PATHOI.
September I992
Table
I. Frequencies of drug combinations Group Control group Vincristine group
I
Drug combination
i ~~~~-- n
-_____-_-
40
To 100.0 52.5 32.5 2.5 2.5 10.0
20 21 13 1 I 4
Cyclophosphamide, methotrexate, S-fluorouracil CMFVP CMFVP + tamoxifen* Alternating MOPP-ABVD MOPP ABV hybrid Bleomycin, doxorubicin, cyclophosphamide, vincristine, prednisone ..____.._
--_
_____.-____
100.0
CMF: Cyclophosphamide, methotrexate, 5-fluorouracil VP: Vincristine, prednisone AT: Tamoxifen; (doxorubicin was added in week 9 of treatment and was not relevant to this study). MOPP ABVD: Nitrogen mustard, vincristine, procarbazine, prednisone; doxorubicin, bleomycin, vinblastine, dacarbazine MOPP ABV HYBRID: Nitrogen mustard, vincristine, procarbazine, prednisone; doxorubicin, bleomycin, vinblastine, hydrocortisone BACOP: Bleomycin, doxorubicin, cyclophosphamide, vincristine, prednisone
tions are shown in Table I. Twenty-eight patients received 1.4 mg/m2 of vincristine, and 12 patients received 1 mg/m2. The maximum dose of vincristine for all patients was 2 mg. A face-to-face interview wasconducted to complete a questionnaire before the start of the first chemotherapy cycle. The orofacial area was examined, and additional information was obtained from the hospital charts. The orofacial examination and face-to-face interview were repeated weekly for a period of 7 weeks,before the administration of chemotherapy. A pilot study had indicated that, in most patients reporting orofacial pain, this symptom developed approximately 3 days after the administration of vincristine. Therefore a standard telephone interview was conducted 4 days after each administration of chemotherapy. The diagnosis of orofacial pain occurring as a manifestation of vincristine neurotoxicity was made with reference to time of onset, duration, quality of pain, number and location of sites affected, factors producing relief or exacerbation, and previous history (or lack of history) of similar symptoms. Symptoms were excluded if lesionsor concurrent diseasecould be the cause of the orofacial pain. The severity of pain was assessedby self-report. Patients were asked to rate any pain as mild, moderate, or severe,and these assessmentswere validated with reference to analgesic requirements. Control group
The control group included 18 breast cancer patients with a mean age of 45 years (range 31 to 54 years). All were receiving treatment with cyclophosphamide, methotrexate, and fluorouracil (Table I). Patients received baseline face-to-face interviews and
examinations on days 1 and 8 of chemotherapy. An additional self-administered questionnaire was completed to report oral signs and symptoms. Data analysis
Variables were dichotomized when necessarywith reference to mean or median values. The Statistical Package for the Social Scienceswas used to produce descriptive statistics. Fisher’s Exact Test (Epistat) and chi-square analysis were used to assessthe statistical association of the predictor and outcome variables.‘2 RESULTS
Fifty-five percent (22/40) of the patients receiving vincristine reported orofacial pain that was attributed to vincristine neurotoxicity. Of these 22 patients, 20 reported orofacial pain in the first week of treatment (Table II). One patient in the control group had pain (burning tongue) during the first week of treatment. When this complaint occurred in the vincristine group, it was not included as a manifestation of neurotoxicity. The mean time of onset of orofacial pain was day 4 of the first chemotherapy cycle (range day 1 to day 5). Onset was usually sudden, and the pain usually lasted for 2 days. Pain was frequently bilateral; only twopatientsdescribedaunilateraldistribution. Eighty percent of affected patients had pain from three or more sites. The distribution of pain is shown in Table III. In many instances the symptoms were unique in the experience of individual patients. The pain was usually described as an ache or throb and could be excruciating, necessitating the use of analgesics in 35% of all patients (14/40). Fifty percent of affected
Orofacial pain with vincristine
Volume 74 Number 3
301
Table II. Frequencies of patients reporting orofacial pain during weeks 1 through 7 of chemotherapy with
vincristine No. (W) of patients reporting orofacial 1
2
3
4
5
6
7
9 (22.5) 5 (12.5) 6 (15.0) 20 (50.0) 40 (100.0)
0 0 2 38 40
0 0 4 36 zi
0 0
0 0
0 0
0 0
2 38 40
2 38 40
2 38 40
1 37 38*
Pain Severe
Moderate Mild None Total
pain during wk of therapy
*Two patients lost to follow-up.
patients (11/22) obtained pain relief with analgesics (usually acetominophen-caffeine-codeine combinations), but analgesia was ineffective in three cases. The pain was exacerbated by chewing (28%), swallowing (8%), drinking (5%) opening and closing the mouth (8%), carbonated drinks (8%), and cold drinks (5%) in affected patients. The associations between the more interesting predictor variables and the presenceof orofacial pain occurring as a manifestation of vincristine neurotoxicity are shown in Table IV. DISCUSSION
Neurotoxic effects have been documented frequently in patients receiving vincristine. There are recent reports of neurotoxicity affecting the peripheral nervous system in 94% and 98% of patients receiving vincristine in a clinical trial of cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone (CMFVP), and CMFVP plus doxorubicin and tamoxifen. Neurotoxicity affecting the central nervous system was noted in 82% and 84% of patients respectively. In the samestudy acute vincristine neurotoxicity (characterized by a combination of jaw pain, abdominal pain with or without paralytic ileus, and bone pain) was severeenough to necessitate hospitalization in 5% of patients receiving 1.4 mg/m2 of vincristine and 0.5% of patients receiving 1 mg/m2 of vincristine.13 The high frequency of neurotoxicity in patients receiving vincristine was reflected in our study population and in 3 of 40 participants (8%) paralytic ileus developed.These three patients all had orofacial pain before this event. An investigation of orofacial pain as a predictor of paralytic ileus was not possible in this study because of the sample size. Previous reports of vincristine neurotoxicity affecting the orofacial region usually describejaw pain. The results of this study show that pain after vincristine administration may occur in the distribution of the trigeminal and glossopharyngeal nerves, and multiple sites are usually affected in individual patients.
Table Ill. Distribution of orofacial pain during first
7 weeks of cancer chemotherapy with vincristine (n = 40) Site
No. (%) of patients a$ected
Temporomandibular joint Mandible Throat Ears Mandibular teeth Maxillary teeth Maxilla Antra Tongue Neck* Around eyes Mouth Lips Edentulous ridges?
15 (37.5) 15 (37.5) 13 (32.5) 13 (32.5) 13 (32.5) II (27.5) 10 (25.0) 7 (17.5) 5 (12.5) 5 (12.5) 3 (7.5) 2 (5.0) 1 (2.5) 1 (2.5)
*Limited to area between angle of mandible and cricoid. ?Patient described pain as “toothache.”
Throat pain and dysphagia have been previously reported as manifestations of vincristine neurotoxicity. 2,5,7 Many patients had sore throats, but because this is such a frequent occurrence in the general population, it was not reported as neurotoxicosis unless other symptoms resulting from neurotoxicity were present, and no other causes were obvious (e.g., inflammation or concurrent viral illness). Some isolated casesof sore tongue were similarly not included as neurotoxic events. The number of episodesof painful throat and painful tongue were far higher in the first week of treatment compared with subsequent cycles. This reflects the reduction in neurotoxic events that occurred after the first week of therapy and suggeststhat neurotoxicity may have beenunderreported in these sites. No symptoms occurring in the control group were comparable with those attributed to vincristine neurotoxicity. The control group was comparable in age; all were female, compared with 92% female in the
302
McCarthjJ
and Skillings
Table IV. Association between patient characteristics and orofacial pain during Hurst7 weeks 01 chemotherapy with vincristine Patients I-Variable
I
with pain
~~~
I ti
%
RR
p value
IO/l3 8/lS 4112
76.9 53.3 33.3
2.3*
0.09
919 13/31
IOO.0 41.9
2.4
0.002t
14120 8/20
70.0 40.0
I.8
0.06
9/ll I3129
81.8 44.8
1.8
0.04$
16123 6117
69.6 35.3
2.0
0.034
Age (yr)
28-39 40-s I 52-63 Marital status Unmarried Married Education (yr) 212
OF WESTERN
BSc, MD, FRCPC, MSC,~
ONTARIO
This prospective cohort study investigated orofacial pain occurring as a manifestation of vincristine neurotoxicity. Forty cancer patients (28 to 63 years of age) receiving vincristine were given baseline interviews and orofacial examinations, which were repeated weekly for 7 weeks of treatment. Twenty-two patients (55%) had neurotoxicity manifesting as orofacial pain. Onset was usually 3 days after vincristine administration; mean duration was 2 days. Twenty patients (50%) were affected in the first week: nine (22%) with severe and five (12%) with moderate pain. Symptoms were mild and infrequent in subsequent weeks. Eighteen control patients receiving chemotherapy without vincristine had no comparable orofacial symptoms. Multiple sites in the distribution of the trigeminal and glossopharyngeal nerves were affected: primarily the temporomandibular joint, mandible, throat, ears, and mandibular teeth. The frequency of orofacial pain increased with younger age. Pain was significantly associated with smaller body surface area (p < 0.05) indicating a dose-related toxicity, and with sociodemographic variables including smoking (p < 0.05). (ORAL SURC ORAL MED ORAL PATHOL 1992;74:299-304)
T
here has been an increasing number of reports of acute vincristine neurotoxicity that include effects on the trigeminal nerve.l-4 Jaw pain, which can be very severe,has been the most consistently reported manifestation. It can occur within hours of the administration of vincristine and can resolve spontaneously within days.‘, S* Transient dental pain9 and throat pain59lo have also been reported. The head and neck manifestations of neurotoxicity resulting from cancer chemotherapeutic agents have been reviewed, and the frequencies of symptoms of vincristine neurotoxicity other than pain have been presented elsewhere.” Kaplan and Wiernik6 reviewed the neurotoxicity of antitumor agents. Chemotherapeutic agents other than vincristine cause neurotoxicity, but the use of these agents has not been associated with orofacial pain, although severejaw pain has been noted after the administration of vinblastine. aAssistant Professor, Division of Oral Biology, Faculty of Dentistry. bAssociate Professor, Department of Oncology, and London Regional Cancer Centre. 7/13/34109
The specific objectives of this study were (1) to measure the frequency of orofacial pain occurring as a manifestation of neurotoxicity in patients receiving cancer chemotherapy with vincristine and (2) to identify factors associatedwith orofacial pain occurring as a manifestation of neurotoxicity in patients receiving cancer chemotherapy with vincristine. METHODS
Consecutive cancer patients who were scheduled to start combination chemotherapy were eligible for inclusion in the study. Exclusion criteria were previous chemotherapy, radiotherapy to the head and neck, age of more than 70 years, minors, inadequate renal function (serum creatinine >140 pmol/L), white blood cell count 35 pmol/L), mental incompetence or psychiatric disorders, and no informed consent. Vincristine
group
Forty patients, with a mean age of 45 years (range 28 to 63 years) were enrolled. This study population has been previously described.” The drug combina299
300
McCarthy
and Skillings
OKU
Sum7 ORAL MOD ORAL
PATHOI.
September I992
Table
I. Frequencies of drug combinations Group Control group Vincristine group
I
Drug combination
i ~~~~-- n
-_____-_-
40
To 100.0 52.5 32.5 2.5 2.5 10.0
20 21 13 1 I 4
Cyclophosphamide, methotrexate, S-fluorouracil CMFVP CMFVP + tamoxifen* Alternating MOPP-ABVD MOPP ABV hybrid Bleomycin, doxorubicin, cyclophosphamide, vincristine, prednisone ..____.._
--_
_____.-____
100.0
CMF: Cyclophosphamide, methotrexate, 5-fluorouracil VP: Vincristine, prednisone AT: Tamoxifen; (doxorubicin was added in week 9 of treatment and was not relevant to this study). MOPP ABVD: Nitrogen mustard, vincristine, procarbazine, prednisone; doxorubicin, bleomycin, vinblastine, dacarbazine MOPP ABV HYBRID: Nitrogen mustard, vincristine, procarbazine, prednisone; doxorubicin, bleomycin, vinblastine, hydrocortisone BACOP: Bleomycin, doxorubicin, cyclophosphamide, vincristine, prednisone
tions are shown in Table I. Twenty-eight patients received 1.4 mg/m2 of vincristine, and 12 patients received 1 mg/m2. The maximum dose of vincristine for all patients was 2 mg. A face-to-face interview wasconducted to complete a questionnaire before the start of the first chemotherapy cycle. The orofacial area was examined, and additional information was obtained from the hospital charts. The orofacial examination and face-to-face interview were repeated weekly for a period of 7 weeks,before the administration of chemotherapy. A pilot study had indicated that, in most patients reporting orofacial pain, this symptom developed approximately 3 days after the administration of vincristine. Therefore a standard telephone interview was conducted 4 days after each administration of chemotherapy. The diagnosis of orofacial pain occurring as a manifestation of vincristine neurotoxicity was made with reference to time of onset, duration, quality of pain, number and location of sites affected, factors producing relief or exacerbation, and previous history (or lack of history) of similar symptoms. Symptoms were excluded if lesionsor concurrent diseasecould be the cause of the orofacial pain. The severity of pain was assessedby self-report. Patients were asked to rate any pain as mild, moderate, or severe,and these assessmentswere validated with reference to analgesic requirements. Control group
The control group included 18 breast cancer patients with a mean age of 45 years (range 31 to 54 years). All were receiving treatment with cyclophosphamide, methotrexate, and fluorouracil (Table I). Patients received baseline face-to-face interviews and
examinations on days 1 and 8 of chemotherapy. An additional self-administered questionnaire was completed to report oral signs and symptoms. Data analysis
Variables were dichotomized when necessarywith reference to mean or median values. The Statistical Package for the Social Scienceswas used to produce descriptive statistics. Fisher’s Exact Test (Epistat) and chi-square analysis were used to assessthe statistical association of the predictor and outcome variables.‘2 RESULTS
Fifty-five percent (22/40) of the patients receiving vincristine reported orofacial pain that was attributed to vincristine neurotoxicity. Of these 22 patients, 20 reported orofacial pain in the first week of treatment (Table II). One patient in the control group had pain (burning tongue) during the first week of treatment. When this complaint occurred in the vincristine group, it was not included as a manifestation of neurotoxicity. The mean time of onset of orofacial pain was day 4 of the first chemotherapy cycle (range day 1 to day 5). Onset was usually sudden, and the pain usually lasted for 2 days. Pain was frequently bilateral; only twopatientsdescribedaunilateraldistribution. Eighty percent of affected patients had pain from three or more sites. The distribution of pain is shown in Table III. In many instances the symptoms were unique in the experience of individual patients. The pain was usually described as an ache or throb and could be excruciating, necessitating the use of analgesics in 35% of all patients (14/40). Fifty percent of affected
Orofacial pain with vincristine
Volume 74 Number 3
301
Table II. Frequencies of patients reporting orofacial pain during weeks 1 through 7 of chemotherapy with
vincristine No. (W) of patients reporting orofacial 1
2
3
4
5
6
7
9 (22.5) 5 (12.5) 6 (15.0) 20 (50.0) 40 (100.0)
0 0 2 38 40
0 0 4 36 zi
0 0
0 0
0 0
0 0
2 38 40
2 38 40
2 38 40
1 37 38*
Pain Severe
Moderate Mild None Total
pain during wk of therapy
*Two patients lost to follow-up.
patients (11/22) obtained pain relief with analgesics (usually acetominophen-caffeine-codeine combinations), but analgesia was ineffective in three cases. The pain was exacerbated by chewing (28%), swallowing (8%), drinking (5%) opening and closing the mouth (8%), carbonated drinks (8%), and cold drinks (5%) in affected patients. The associations between the more interesting predictor variables and the presenceof orofacial pain occurring as a manifestation of vincristine neurotoxicity are shown in Table IV. DISCUSSION
Neurotoxic effects have been documented frequently in patients receiving vincristine. There are recent reports of neurotoxicity affecting the peripheral nervous system in 94% and 98% of patients receiving vincristine in a clinical trial of cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone (CMFVP), and CMFVP plus doxorubicin and tamoxifen. Neurotoxicity affecting the central nervous system was noted in 82% and 84% of patients respectively. In the samestudy acute vincristine neurotoxicity (characterized by a combination of jaw pain, abdominal pain with or without paralytic ileus, and bone pain) was severeenough to necessitate hospitalization in 5% of patients receiving 1.4 mg/m2 of vincristine and 0.5% of patients receiving 1 mg/m2 of vincristine.13 The high frequency of neurotoxicity in patients receiving vincristine was reflected in our study population and in 3 of 40 participants (8%) paralytic ileus developed.These three patients all had orofacial pain before this event. An investigation of orofacial pain as a predictor of paralytic ileus was not possible in this study because of the sample size. Previous reports of vincristine neurotoxicity affecting the orofacial region usually describejaw pain. The results of this study show that pain after vincristine administration may occur in the distribution of the trigeminal and glossopharyngeal nerves, and multiple sites are usually affected in individual patients.
Table Ill. Distribution of orofacial pain during first
7 weeks of cancer chemotherapy with vincristine (n = 40) Site
No. (%) of patients a$ected
Temporomandibular joint Mandible Throat Ears Mandibular teeth Maxillary teeth Maxilla Antra Tongue Neck* Around eyes Mouth Lips Edentulous ridges?
15 (37.5) 15 (37.5) 13 (32.5) 13 (32.5) 13 (32.5) II (27.5) 10 (25.0) 7 (17.5) 5 (12.5) 5 (12.5) 3 (7.5) 2 (5.0) 1 (2.5) 1 (2.5)
*Limited to area between angle of mandible and cricoid. ?Patient described pain as “toothache.”
Throat pain and dysphagia have been previously reported as manifestations of vincristine neurotoxicity. 2,5,7 Many patients had sore throats, but because this is such a frequent occurrence in the general population, it was not reported as neurotoxicosis unless other symptoms resulting from neurotoxicity were present, and no other causes were obvious (e.g., inflammation or concurrent viral illness). Some isolated casesof sore tongue were similarly not included as neurotoxic events. The number of episodesof painful throat and painful tongue were far higher in the first week of treatment compared with subsequent cycles. This reflects the reduction in neurotoxic events that occurred after the first week of therapy and suggeststhat neurotoxicity may have beenunderreported in these sites. No symptoms occurring in the control group were comparable with those attributed to vincristine neurotoxicity. The control group was comparable in age; all were female, compared with 92% female in the
302
McCarthjJ
and Skillings
Table IV. Association between patient characteristics and orofacial pain during Hurst7 weeks 01 chemotherapy with vincristine Patients I-Variable
I
with pain
~~~
I ti
%
RR
p value
IO/l3 8/lS 4112
76.9 53.3 33.3
2.3*
0.09
919 13/31
IOO.0 41.9
2.4
0.002t
14120 8/20
70.0 40.0
I.8
0.06
9/ll I3129
81.8 44.8
1.8
0.04$
16123 6117
69.6 35.3
2.0
0.034
Age (yr)
28-39 40-s I 52-63 Marital status Unmarried Married Education (yr) 212
